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  • Review
  • Open Access

Decoding the role of TET family dioxygenases in lineage specification

Epigenetics & Chromatin201811:58

https://doi.org/10.1186/s13072-018-0228-7

  • Received: 27 July 2018
  • Accepted: 28 September 2018
  • Published:

Abstract

Since the discovery of methylcytosine oxidase ten-eleven translocation (TET) proteins, we have witnessed an exponential increase in studies examining their roles in epigenetic regulation. TET family proteins catalyze the sequential oxidation of 5-methylcytosine (5mC) to oxidized methylcytosines including 5-hydroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxylcytosine. TETs contribute to the regulation of lineage-specific gene expression via modulating DNA 5mC/5hmC balances at the proximal and distal regulatory elements of cell identity genes, and therefore enhance chromatin accessibility and gene transcription. Emerging evidence suggests that TET dioxygenases participate in the establishment and/or maintenance of hypomethylated bivalent domains at multiple differentiation-associated genes, and thus ensure developmental plasticity. Here, we review the current state of knowledge concerning TET family proteins, DNA hydroxymethylation, their distribution, and function in endoderm, mesoderm, and neuroectoderm specification. We will summarize the evidence pertaining to their crucial regulatory roles in lineage commitment and development.

Keywords

  • Lineage specification
  • TET
  • 5hmC
  • 5mC
  • Bivalent promoter
  • Enhancer

Background

DNA methylation and the recently identified hydroxymethylation are essential epigenetic modifications in cells. DNA methylation is catalyzed by DNA cytosine-5-methyltransferases (DNMTs) via transferring a methyl group to the 5′ position of cytosine to form 5-methylcytosine (5mC). Heavily methylated DNA is often associated with repressed gene expression. In addition, DNA methylation can be actively demethylated by DNA methylcytosine dioxygenases, the ten-eleven translocation (TET) proteins, through oxidizing 5mC into 5-hydroxymethylcytosine (5hmC) and further to 5-formylcytosine (5fC) and then to 5-carboxylcytosine (5caC). Finally, 5fC and 5caC are removed by thymine DNA glycosylase (TDG) and cytosine is replaced by base excision repair (BER) [15]. Successful oxidation of 5mC by TET proteins influences various biological properties such as chromatin accessibility, nucleosome positioning, genomic stability, and rates of gene transcription [69]. TET proteins hence serve as important epigenetic modifiers that participate in a number of biological processes including embryogenesis, lineage specification, and disease development. Herein, we specifically review how TET proteins and their enzymatic products contribute to the regulation of cell lineage commitment and development.

Structural basis of TET family proteins

TET proteins are widely expressed in various organisms including human, mouse, Xenopus, and zebrafish [6, 1014]. The three TET family members (TET1, TET2, and TET3) share a highly conserved catalytic domain at the C-termini, which comprises cysteine-rich and double-stranded β-helix (DSBH) regions [15, 16]. The DSBH region contains ferrous (Fe2+) and α-ketoglutarate (α-KG) binding sites that are critical for TET catalytic activity [17, 18]. TET1 and TET3 both possess a zinc finger cysteine-X-X-cysteine (CXXC) domain at the N-termini, which allows them to bind to cytosine and its modified forms (e.g., 5mC, 5hmC, 5fC, and 5caC) in DNA [6, 19, 20]. Although TET2 does not encode the CXXC domain, it targets deoxynucleotides through another CXXC-containing protein known as IDAX or CXXC4. Therefore, TET2 appears to bind to DNA in a similar fashion as TET1 and TET3 [21]. Recently, a CXXC-domain deficient short form of TET1 (TET1S) has been identified in both mouse and human somatic cells [22, 23]. TET1S retains reduced catalytic activity of TET dioxygenase and displays a weaker binding affinity for DNA [22]. Despite their differences in DNA binding properties, these TET isoforms are comparable in terms of 5mC oxidation capability.

Dynamic distribution of TETs and 5hmC during development

The three TET family members have distinct expression patterns among different cell types and are tightly regulated during development [2426]. TET1 protein is highly expressed in both human and mouse embryonic stem cells (ESCs), whereas TET2 is expressed at extremely low levels in human ESCs similar to TET3 in mouse ESCs [2628]. The expression levels of TET proteins change dynamically during development. For instance, TET3 is expressed at high levels in oocytes and zygotes, and undergoes rapid downregulation in two-cell-stage embryos [29]. It has been shown that TET3 expression increases dramatically in human ESC-derived neuroectoderm and pancreatic endoderm [24, 28], which is consistent with its progressive increase in mouse embryos from e6.5 to e9.5 [30]. In contrast, TET2 is widely expressed in a variety of somatic organs and cell types, especially in hematopoietic cells [31]. More interestingly, recent studies have illustrated that two TET1 isoforms also display distinct expression patterns, in which the full-length isoforms of TET1 are preferentially expressed in ESCs, early embryos, and primordial germ cells (PGC), while the short form of TET1 (TET1S) is restricted to somite cells and overexpressed in cancer [22, 23, 32]. An isoform switch of TET1 has been implicated in influencing gametic imprinting, PGC development, and epigenetic memory erasure [22].

Since the discovery of TET family dioxygenases, studies examining the function of DNA hydroxymethylation have exponentially increased. Emerging evidence indicates that 5hmCs are enriched at low-to-intermediate CpG density regions of promoters and enhancers of developmental regulatory genes [3342]. Similar to TET family proteins, the distribution of 5hmC is dynamically changed and positively correlated with active gene transcription during lineage specification [35, 43, 44]. For example, high levels of 5hmC are found in ESCs and in the central nervous system [16, 45]. Global 5hmC levels decrease during ESCs differentiation toward neuroectoderm fate, while enrichment of 5hmC at the gene body of transcriptionally active genes is identified in neural progenitor cells (NPCs) [43, 44]. When NPCs further differentiate into neurons, overall 5hmC increases are accompanied by a loss of H3K27me3 at promoters of genes that are important for neuronal function [34]. Likewise, a human ESC-based model of pancreatic differentiation reveals that global 5hmC levels rapidly decrease at the first step toward definitive endoderm, then gradually increase toward pancreatic endoderm specification. 5hmC enriching peaks significantly overlap with poised and active enhancers, as well as the boundaries of hypomethylated functional genomic regions [28]. Furthermore, enrichment of 5hmC at tissue-specific enhancers has also been demonstrated in cardiomyocyte and hematopoietic cell differentiation [10, 35, 46]. Other than at promoters and enhancers, enrichment of 5hmC is also found over the gene bodies of actively transcribed genes [35, 36, 47]. Taken together, these studies suggest that expression of TET family proteins and distribution of 5hmC is differentially regulated to meet the needs of cellular functions during lineage commitment.

Mechanisms of TET family proteins in the regulation of gene transcription

The establishment of cellular identities requires precise control of gene expression. Mounting evidence suggests that TET proteins work as epigenetic players to alter DNA methylation, histone modification, and chromatin accessibility, which regulate the transcription of key developmental genes. Strikingly, promoters, enhancers, and DNase I-hypersensitive sites accumulate significantly more 5mC in Tet1, Tet2, and Tet3 triple knockout mouse ESCs, suggesting that these gene regulatory regions are the major targets of TETs [13, 48, 49]. In the following subsections, we discuss the current mechanistic understanding of how TET proteins regulate lineage-specific gene expression.

Maintenance of hypomethylated promoters of developmental genes

Accumulated evidence indicates that DNA methylation status at promoter regions influences gene transcription [50]. Promoter hypermethylation is believed to contribute to the establishment of a transcriptionally poised/inactive state [50]. For example, pluripotent genes, such as OCT4, are actively expressed in human ESCs and suppressed by promoter hypermethylation upon differentiation [44]. It has been widely documented that genetic ablation of TET induces promoter hypermethylation and aberrant gene expression in multiple lineage differentiation systems [6, 25, 27, 38, 5153]. For example, TET2 is required for the maintenance of NANOG expression in the spontaneous differentiation of mesodermal lineage cells from human ESCs. TET2 ChIP-seq revealed that TET2 associated with the NANOG promoter prevents DNA methylation [27]. In helper T cell differentiation, Tet2 is recruited to the promoters of cytokine genes in a lineage-specific transcriptional factor-dependent manner, which stimulates active DNA demethylation and expression of these cytokine genes [38]. TET1 and TET3 also regulate DNA methylation status in the promoter regions. For instance, Tet3 directly binds to the promoters of genes critical for neural development in Xenopus, such as Pax6, Rx, and Ngn2, and sustains high levels of 5hmC at promoters [6]. Furthermore, simultaneous deletion of Tet2 and Tet3 downregulates P2rX7 expression along with reduction of 5hmC at the P2rX7 promoter during bone marrow mesenchymal stem cell differentiation [53], indicating that TET-mediated rapid and specific oxidation of 5mC at promoter loci is biologically relevant.

More interestingly, TET-mediated DNA demethylation has been suggested in association with the establishment and/or maintenance of bivalent promoters of developmental genes, in which H3K4me3 and H3K27me3 histone modifications take place simultaneously [14, 54]. In general, bivalent promoters of developmental genes are hypomethylated in ESCs [55]. They are preferentially repressed by trimethylation of histone H3 at lysine 27, which is easier to be reversed than DNA methylation. These low-methylated genetic loci can extend beyond promoter regions, forming H3K27me3-marked DNA methylation valleys (DMVs) that provide binding sites for a large set of transcription factors to mediate complex regulation during development [56]. It has been recently shown that TET proteins and Polycomb Repressive Complex 2 (PRC2), which is responsible for H3K27 methylation, can recruit each other to maintain a hypomethylated status at bivalent promoters and DMVs [5759]. In addition, TETs can interact with OGT (O-linked β-N-acetylglucosamine transferase), which enhances methylation of histone H3 at lysine 4 by promoting the binding of a component of the H3K4 methyltransferase SET1/COMPASS complex to active promoters [60]. It has been further demonstrated that overexpression of TET2, but not the catalytically inactive TET2, results in an increase in 5hmC at a particular set of key developmental gene promoters, which is sufficient to promote DNA demethylation and de novo bivalent modifications [54]. This discovery was subsequently supported by a recent report which illustrated that TETs safeguard bivalent promoters of many lineage determinants, such as FOXA2, GATA2, PAX6, and SOX17, by preventing their aberrant hypermethylation to ensure developmental competency [14]. Together, these studies suggest that TET-mediated DNA demethylation retains developmental plasticity at the promoters and/or DMVs of developmentally important genes, and therefore ensure robust induction of lineage-specific transcription upon differentiation (Fig. 1).
Fig. 1
Fig. 1

The role of TET proteins on lineage-specific bivalent promoters and enhancers. a In the presence of TET dioxygenases, PRC2 recruits TETs to bivalent promoters to maintain their hypomethylated status. In the absence of TETs, binding of DNMT3B at the bivalent promoters causes de novo DNA methylation, which leads to stable gene silencing and loss of developmental plasticity. b A model of TET-mediated enhancer priming and activation. Upon differentiation, pioneer transcription factors that are not sensitive to DNA modifications can bind to distal enhancers of lineage-specific genes and recruit TETs to demethylate methylcytosines. Other epigenetic modifiers, such as p300 and SET1/COMPASS, subsequently bind to these sites and establish poised (H3K4me1) and active (H3K27ac) enhancers, which in turn increases chromatin accessibility and allow other transcription factors binding to occur

Regulation of chromatin accessibility and enhancer architecture

In addition to facilitate promoter hypomethylation, TET proteins also play critical roles in regulating chromatin accessibility and enhancer architecture (Fig. 1). 5hmC co-localizes with enhancers and open chromosome regions during different biological processes, such as B cell differentiation and pancreatic endocrine differentiation [7, 28, 61]. By examining genome-wide DNA methylation and hydroxymethylation in the context of Tet2 deletion in mESCs, Ren and colleagues have found that depletion of Tet2 leads to enhancer hypermethylation, accompanied by the loss of active enhancer mark H3K27ac and delayed the induction of Slit3, Lmo4, and Irx3 upon differentiation to a neural progenitor fate [62]. A similar observation has been made in cardiomyocytes where deletion of Tet2 causes loss of 5hmC at enhancers and is accompanied by extensive elevation of DNA methylation, reduction of H3K27ac, and impaired gene expression during heart development [10]. Re-expression of Tet2 catalytic domain in Tet2/3 double knockout pro-B cells restores chromatin accessibility at a genome-wide level as well as at the Igκ enhancer [7]. In agreement with the above studies, application of TET inhibitor dimethyloxalylglycine (DMOG) reduces chromatin accessibility at specific enhancers of P19 embryonic carcinoma cells when differentiated to NPCs [63]. These data implicate the functional relevance of TETs and TET-mediated 5hmC to chromatin accessibility at distal regulatory elements, particularly enhancers. Although the precise molecular mechanisms remain unclear, epigenetic readers of 5hmC, such as MeCP2 (methyl-CpG-binding protein 2), might constitute a mechanism of TET-regulated chromatin opening [64].

In addition to chromatin accessibility, TETs may also contribute to enhancer priming. Prior to activation, the enhancer region is methylated and not accessible to general transcription factors. However, pioneer transcription factors, such as FOXA1, MEIS1, and PBX1, preferentially bind to oligonucleotide probes which contain methylated cytosines [63, 65]. It has also been suggested that pioneer transcription factors can physically interact with TETs which catalyze oxidation of 5mC at gene regulatory regions [7, 66, 67]. For example, pioneer transcription factors, PU.1, recruit Tet2 proteins to the Igκ enhancer to facilitate DNA demethylation during early B cell maturation [7]. Furthermore, removal of 5mC or deposition of 5hmC coincides with increased accessibility of enhancers and monomethylation of H3K4 [12, 28, 63]. Accordingly, H3K4 methyltransferases are repelled by 5mC [68, 69], indicating that TET-mediated DNA demethylation is necessary for the recruitment of H3K4 methyltransferases to prime enhancers. Additionally, it has been demonstrated that TETs can recruit SET1/COMPASS H3K4 methyltransferase as well as histone acetyltransferase p300 to gene regulatory regions [38, 60]. Therefore, H3K4 monomethyltransferases MLL3/4, which are COMPASS family members, might also interact with TETs and become recruited to enhancer regions [70].

Despite their plausible contribution to chromatin architecture, TETs may regulate gene transcription by interfering with RNA polymerization and RNA splicing. In CD4+ T cells, TET1 and TET2 alter CTCF-dependent alternative pre-mRNA splicing through oxidation of 5mC to 5hmC and 5caC at corresponding intragenic CTCF-binding sites in the PTPRC (protein tyrosine phosphatase CD45) locus [71, 72]. Additionally, it has been suggested that oxidation derivatives of 5hmC are concentrated on the gene bodies of transcribed genes and support transcriptional consistency [35, 47].

TET dioxygenases modulate cell fate commitment

Growing evidence confirms that TET family proteins are important regulators for embryogenesis. Tet1/2/3 triple knockout mice are embryonic lethal with severe gastrulation defects during embryogenesis [13, 30, 48]. Although the formation of three germ layers is initiated, Tet-null mouse embryos cannot further develop, accompanied by impaired patterning of axial mesoderm, neuroectoderm, and definitive endoderm [13, 30]. Furthermore, knockdown of TET2 skews spontaneous differentiation of human ESCs into neuroectoderm with the loss of mesoderm and endoderm [27], while inactivation of Tet2 in mouse hematopoietic stem cells leads to an increase in the granulocytic and monocytic population [31]. Thus, deficiency of TET proteins disturbs the 5mC and 5hmC landscapes, which causes differentiation to switch from one to another lineage [30, 61, 73, 74]. These studies illustrate the critical function of TET family proteins in development. Below, we will discuss the roles of TET proteins in each lineage commitment (Table 1).
Table 1

Phenotypes resulting from the depletion of TETs in ectoderm, mesoderm, and endoderm lineages

Lineage

System

TET isoform

Phenotype

References

Ectoderm

Human ESCs

TET1/2/3 triple knockout

Form fewer PAX6+ neuroectoderm cells

[14]

 

Neuron stem cells

Tet1 or Tet2 knockdown

Reduce proliferation of neuron stem cells

[90]

 

Cortex

Tet2 or Tet3 knockdown

Abnormal accumulation of cell clusters along the radial axis in the intermediate zone and ventricular zone

[34]

 

Cerebellar granule cells

Tet1/3 double knockdown

Impair dendritic arborization of cerebellar granule cells

[77]

 

Mouse ESCs

Tet3 knockout

Apoptosis of neuron progenitor cells and reduce terminal differentiated neurons

[24]

 

Neurons

Tet1 knockout

Increase hippocampal long-term depression and impair memory extinction

[75]

 

Neurons

Tet1 overexpression

Promote neurogenesis

[91]

 

Retinal neurons

Tet2/3 double knockout

Defects in retinal cells terminal differentiation

[92]

 

Cortical neurons

Tet2 knockdown

Reduce neuronal cells survival

[93]

 

Head

Tet1 mutation

Defects in neural tube closure

[94]

 

Eye and neural

Tet3 knockdown

Eye malformations and small head

[6]

 

Oligodendrocyte precursor cells

Tet1, Tet2, or Tet3 knockdown

Reduce mature oligodendrocytes

[95]

 

Olfactory sensory neurons

Tet3 overexpression

Disturb axon targeting and olfactory receptor expression

[47]

 

Dental pulp cells

TET1 knockdown

Prevent the proliferation and differentiation of dental pulp cells

[96]

Mesoderm

Hematopoietic stem cells

Tet2 knockout

Enhance self-renewal of hematopoietic stem cells, expansion of myeloid progenitors

[97]

 

Bone marrow cells

Tet2 knockdown

Enhance self-renewal of hematopoietic stem cells, expansion of myeloid progenitors

[31]

 

Hematopoietic stem cells

Tet2/3 double knockout

Loss of hematopoietic stem cell-derived blood cells

[98]

 

Human ESCs

TET2 knockdown

Impair hematopoietic cell differentiation

[27]

 

T cells

Tet2/3 double knockout

Form more iNKT cell in the young mice, and skew major population to NKT17 cells

[74]

 

Regulatory T cells

Tet2/3 double knockout

Less regulatory T cells in the spleen and lymph nodes

[86]

 

Regulatory T cells

Tet1/2 double knockout

Less regulatory T cells in the spleen and lymph nodes

[83]

 

T cells

Tet2 knockout

Impair Th1 and Th17 cells differentiation and cytokine genes induction

[38]

 

T cell

Tet2 knockout

Promote memory CD8+ T cells differentiation after viral infection

[99]

 

B cells

Tet2/3 double knockout

Block progenitor B cells differentiation and maturation

[7, 61]

 

Mast cells

Tet2 knockout

Impair mast cell differentiation, cytokine production, and proliferation

[85]

 

Erythroid cells

TET2 or TET3 knockdown

Delay differentiation of erythroid progenitors and regulate terminal differentiation

[84]

 

Bone marrow mesenchymal stem cells

Tet1/2 double knockout

Increase self-renewal of bone marrow mesenchymal stem cells and reduce osteogenic differentiation

[53]

 

Smooth muscle cell

TET2 overexpression

Convert fibroblasts to smooth muscle cells

[51]

 

Skeletal muscle myoblasts

Tet2 knockdown

Impair myoblast differentiation

[88]

 

Cardiomyocyte

Tet2 knockdown

Downregulate genes related to cardiac muscle contraction and cardiac muscle fiber development

[10]

Endoderm

Intestinal stem cell

Tet1 knockout

Form shorter intestine

[25]

 

T84 colon adenocarcinoma cells

Tet1 knockdown

Dysregulate genes related to cell membrane and extracellular space

[100]

Neuroectoderm lineage specification

The brain is one of the places in mammals with the most abundant 5hmC, suggesting that TET proteins and TET-mediated 5hmC might have significant impacts in neurogenesis. Tet1 knockout mice exhibit defects in neuron function including learning, memory consolidation, storage, and extinction [52, 75, 76]. Ablation of Tet1 leads to downregulation of neuronal activity-regulated genes such as Npas4 [75]. Although Tet1 is highly expressed in multiple regions and cells of the brain like hippocampus, isocortex, and cerebellar granule cells [77, 78], Tet1 knockout does not alter brain morphology. It has been revealed that compensatory upregulations of Tet2 and Tet3 were observed in the Tet1 knockout mouse brain [76]. In addition, overexpression of Tet3 can facilitate the reprogramming of MEFs (mouse embryo fibroblasts) into neuronal cells, which is accompanied with an active demethylation process at the promoters of genes encoding neuron-specific transcription factors such Ascl1, Brn2, and Ngn2 [79]. Therefore, TET family members are functionally redundant in neurogenesis. In the absence of Tet1, other Tet family members can compensate for the activity of Tet1 to regulate neurogenesis.

A recent study from Huangfu’s group has nicely demonstrated that TET1/2/3 triple knockout human ESCs lose their ability to differentiate into PAX6+/SOX1+ neuroectoderm cells, which is mainly caused by aberrant hypermethylation at the PAX6 promoter [14]. In human ESCs, TET1 binding at PAX6 bivalent promoter leads to the progressive oxidation of 5-methylcytosine. In the absence of 5hmC, de novo DNA methyltransferase DNMT3B anchors at PAX6 bivalent promoter P0 and induces promoter hypermethylation, which suppresses PAX6 induction and subsequent neuroectoderm differentiation. Targeted demethylation of the PAX6 P0 promoter by a catalytically inactive Cas9 (dCas9) fused with a TET1 catalytic domain partially restored PAX6 expression and rescued neuron differentiation defects [14]. These results clearly illustrate that TET-mediated hydroxymethylation prevents repressive DNA methylation and ensures key lineage-specific transcription factor expression in neuron differentiation.

Mesoderm lineage specification

TET2 is ubiquitously expressed in multiple hematopoietic cells, and its mutation is frequently found in hematological malignancies [31, 80, 81]. It has been well documented that TET2 is critical for hematopoiesis. In patients who develop chronic myelomonocytic leukemia and carry TET2 mutations in CD34+ hematopoietic progenitor cells, the TET2-mutated CD34+ progenitors preferentially develop into myeloid instead of erythroid cells upon differentiation [82]. Furthermore, it has been shown that single deletion of Tet2 or double deletion of Tet2/3 or Tet1/2 alters T cell, B cell, NKT cell, red blood cell, or mast cell differentiation and maturation [38, 61, 74, 8385]. For instance, genetic depletion of Tet2 perturbs the induction of signature cytokine genes upon differentiation of CD4+ T cells toward helper T (Th) cells, which is associated with differential enrichment of 5hmC and p300 at the promoters of Ifng and Il17 [38]. In contrast, Tet1/Tet2 or Tet2/Tet3 double knockout mice contain less regulatory T (Treg) cells in the spleen. It has been further shown that Tet proteins can demethylate the conserved noncoding sequences (CNS) in Foxp3 loci to maintain the expression of Foxp3 [83, 86]. One of the Foxp3 CNS functions as a super enhancer and docking site for chromatin organizer Satb1 binding [87].

Moreover, TET dioxygenases have also been implicated to play crucial roles during cardiomyocytes and skeletal myoblast differentiation [10, 51, 88]. Knockdown of Tet2 in undifferentiated C2C12 myoblasts significantly reduces the induction of myoblast differentiation-associated genes Myog and myoM with elevated methylation at their promoters [88]. Additionally, TET2 is shown to control the expression of contractile genes, such as SRF, MYOCD, and MYH11, in human coronary artery smooth muscle cells [51]. Similarly, loss of gene expression in smooth muscle cells is correlated with a significant decrease in TET2 binding and 5hmC levels at the promoters of corresponding genes. In cardiomyocyte differentiation, Tet2 knockdown deregulates a large number of genes associated with heart development and contraction. In particular, induction of the key cardiac gene Myh7 is suppressed upon cardiomyocyte differentiation in Tet2 knockdown cells, presumably due to the aberrant methylation at its enhancer [10].

Endoderm lineage specification

To date, functional analyses of TETs and 5hmC in the context of endodermal lineage specification are still limited. In the intestine, Tet1 is highly expressed in intestinal stem cells and positively regulates the expression of Wnt target genes such as Axin2 and Lgr5 [25]. In a model of hepatocyte differentiation from the human hepatic progenitor HepaRG cells, Hernandez-Vargas and colleagues demonstrated that TET1 dioxygenase is necessary for HNF4A promoter P1 demethylation and activation upon hepatocyte differentiation [89]. They found that TET1 binds to the P1 locus via the pioneer transcription factor FOXA2, which is required for the establishment of the hepatocyte program [89]. Additionally, to understand the precise role of TET-mediated hydroxymethylation during pancreatic lineage progression, we recently characterized each lineage intermediate, including definitive endoderm, primitive gut tube, posterior foregut, and pancreatic progenitors, in great detail during their stepwise differentiation from human ESCs [28]. We developed genome-wide maps for each stage, encompassing 5mC/5hmC, gene expression, and chromatin architecture/accessibility. We identified that 5hmC is positively correlated with enhancer activities and chromatin accessibility during pancreatic differentiation [28], and further discovered that TET dioxygenases promoted pancreatic endocrine differentiation but had less effect on the early endoderm formation (unpublished results).

Conclusion and perspectives

In summary, TETs and TET-mediated 5hmC are dynamically redistributed in lineage descendants during development. A substantial number of studies have provided data supporting the role of TET proteins in the establishment of cell identity during differentiation. TET family members alter lineage specification as epigenetic modifiers through their dioxygenase activity to convert 5mC to oxidized methylcytosine. They modulate DNA methylation/hydroxymethylation balance at promoters and enhancers of cell fate-determining genes to further increase chromatin accessibility and facilitate gene transcription in lineage commitment. Strikingly, TET dioxygenases participate in the establishment and/or maintenance of bivalent domains of many differentiation-associated genes, and thusly ensure developmental plasticity. However, direct connections between TET dioxygenases and chromatin architecture are still not clear. Although 5hmC is enriched at distal regulatory elements, how the poised and active enhancer states are influenced by TETs remains elusive. It will be of great interest to identify whether oxidized methylcytosines can act as docking sites and recruit epigenetic readers to modulate histone modifications. Further studies aimed at unraveling the precise role of TET dioxygenases in the control of epigenetic machinery and gene regulation will contribute to the knowledge of how lineage specification is precisely regulated during development.

Abbreviations

TET: 

ten-eleven translocation protein

5mC: 

5-methylcytosine

5hmC: 

5-hydroxymethylcytosine

5fC: 

5-formylcytosine

5caC: 

5-carboxylcytosine

DNMT: 

DNA methyltransferase

TDG: 

thymine DNA glycosylase

BER: 

base excision repair

DSBH: 

double-stranded β-helix

CXXC: 

cysteine-X-X-cysteine

ESCs: 

embryonic stem cells

NPCs: 

neural progenitor cells

DMVs: 

DNA methylation valleys

PRC2: 

Polycomb Repressive Complex 2

OGT: 

O-linked β-N-acetylglucosamine transferase

DMOG: 

dimethyloxalylglycine

H3K27ac: 

acetylation of histone H3 at lysine 27

H3K4me1: 

monomethylation of histone H3 at lysine 4

H3K4me3: 

trimethylation of histone H3 at lysine 4

H3K27me3: 

trimethylation of histone H3 at lysine 27

Declarations

Authors’ contributions

XW and RX wrote the manuscript and prepared the figure and table. GL contributed to critically revising the manuscript at the final stage. RX developed the idea, corrected, and revised the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We thank Dr. Xiaohui Hu and Dr. Garry Wong for constructive comments and critical reading on the manuscript. We apologize to our colleagues whose references were omitted owing to space constraints. Research in the Xie laboratory is supported by grants from the National Natural Science Foundation of China (NSFC 31701276), Macau Science and Technology Development Fund (FDCT 170/2017/A3), and University of Macau Multi-Year Research Grant (MYRG 2016-00065-FHS).

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Not applicable.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Funding

This work was supported by grants from the National Natural Science Foundation of China (NSFC 31701276), Macau Science and Technology Development Fund (FDCT 170/2017/A3), and University of Macau Multi-Year Research Grant (MYRG 2016-00065-FHS) to RX.

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Authors’ Affiliations

(1)
Centre of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China

References

  1. Maiti A, Drohat AC. Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem. 2011;286:35334–8. https://doi.org/10.1074/jbc.C111.284620.View ArticlePubMedPubMed CentralGoogle Scholar
  2. Zhang L, Lu X, Lu J, Liang H, Dai Q, Xu GL, et al. Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA. Nat Chem Biol. 2012;8:328–30. https://doi.org/10.1038/nchembio.914.View ArticlePubMedPubMed CentralGoogle Scholar
  3. Pastor WA, Aravind L, Rao A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol. 2013;14:341–56. https://doi.org/10.1038/nrm3589.View ArticlePubMedPubMed CentralGoogle Scholar
  4. Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PA, Rappsilber J, et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature. 2011;473:343–8. https://doi.org/10.1038/nature10066.View ArticlePubMedPubMed CentralGoogle Scholar
  5. He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011;333:1303–7. https://doi.org/10.1126/science.1210944.View ArticlePubMedPubMed CentralGoogle Scholar
  6. Xu Y, Xu C, Kato A, Tempel W, Abreu JG, Bian C, et al. Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell. 2012;151:1200–13. https://doi.org/10.1016/j.cell.2012.11.014.View ArticlePubMedPubMed CentralGoogle Scholar
  7. Lio CW, Zhang J, Gonzalez-Avalos E, Hogan PG, Chang X, Rao A. Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility. Elife. 2016. https://doi.org/10.7554/elife.18290.View ArticlePubMedPubMed CentralGoogle Scholar
  8. Teif VB, Beshnova DA, Vainshtein Y, Marth C, Mallm JP, Hofer T, et al. Nucleosome repositioning links DNA (de)methylation and differential CTCF binding during stem cell development. Genome Res. 2014;24:1285–95. https://doi.org/10.1101/gr.164418.113.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Kafer GR, Li X, Horii T, Suetake I, Tajima S, Hatada I, et al. 5-Hydroxymethylcytosine marks sites of DNA damage and promotes genome stability. Cell Rep. 2016;14:1283–92. https://doi.org/10.1016/j.celrep.2016.01.035.View ArticlePubMedGoogle Scholar
  10. Greco CM, Kunderfranco P, Rubino M, Larcher V, Carullo P, Anselmo A, et al. DNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy. Nat Commun. 2016;7:12418. https://doi.org/10.1038/ncomms12418.View ArticlePubMedPubMed CentralGoogle Scholar
  11. Ge L, Zhang RP, Wan F, Guo DY, Wang P, Xiang LX, et al. TET2 plays an essential role in erythropoiesis by regulating lineage-specific genes via DNA oxidative demethylation in a zebrafish model. Mol Cell Biol. 2014;34:989–1002. https://doi.org/10.1128/MCB.01061-13.View ArticlePubMedPubMed CentralGoogle Scholar
  12. Bogdanovic O, Smits AH, Mustienes ED, Tena JJ, Ford E, Williams R, et al. Active DNA demethylation at enhancers during the vertebrate phylotypic period. Nat Genet. 2016;48:417–26. https://doi.org/10.1038/ng.3522.View ArticlePubMedPubMed CentralGoogle Scholar
  13. Dai HQ, Wang BA, Yang L, Chen JJ, Zhu GC, Sun ML, et al. TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling. Nature. 2016;538:528–32. https://doi.org/10.1038/nature20095.View ArticlePubMedGoogle Scholar
  14. Verma N, Pan H, Dore LC, Shukla A, Li QV, Pelham-Webb B, et al. TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells. Nat Genet. 2018;50:83–95. https://doi.org/10.1038/s41588-017-0002-y.View ArticlePubMedGoogle Scholar
  15. Iyer LM, Tahiliani M, Rao A, Aravind L. Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle. 2009;8:1698–710. https://doi.org/10.4161/cc.8.11.8580.View ArticlePubMedPubMed CentralGoogle Scholar
  16. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930–5. https://doi.org/10.1126/science.1170116.View ArticlePubMedPubMed CentralGoogle Scholar
  17. Yin R, Mo J, Dai J, Wang H. Nickel(II) inhibits tet-mediated 5-methylcytosine oxidation by high affinity displacement of the cofactor iron(II). ACS Chem Biol. 2017;12:1494–8. https://doi.org/10.1021/acschembio.7b00261.View ArticlePubMedGoogle Scholar
  18. Xiao MT, Yang H, Xu W, Ma SH, Lin HP, Zhu HG, et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Gene Dev. 2012;26:1326–38. https://doi.org/10.1101/gad.191056.112.View ArticlePubMedGoogle Scholar
  19. Xu Y, Wu F, Tan L, Kong L, Xiong L, Deng J, et al. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell. 2011;42:451–64. https://doi.org/10.1016/j.molcel.2011.04.005.View ArticlePubMedPubMed CentralGoogle Scholar
  20. Jin SG, Zhang ZM, Dunwell TL, Harter MR, Wu X, Johnson J, et al. Tet3 reads 5-carboxylcytosine through its CXXC domain and is a potential guardian against neurodegeneration. Cell Rep. 2016;14:493–505. https://doi.org/10.1016/j.celrep.2015.12.044.View ArticlePubMedPubMed CentralGoogle Scholar
  21. Ko M, An J, Bandukwala HS, Chavez L, Aijo T, Pastor WA, et al. Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX. Nature. 2013;497:122–6. https://doi.org/10.1038/nature12052.View ArticlePubMedPubMed CentralGoogle Scholar
  22. Zhang W, Xia W, Wang Q, Towers AJ, Chen J, Gao R, et al. Isoform switch of TET1 regulates DNA demethylation and mouse development. Mol Cell. 2016;64:1062–73. https://doi.org/10.1016/j.molcel.2016.10.030.View ArticlePubMedGoogle Scholar
  23. Good CR, Madzo J, Patel B, Maegawa S, Engel N, Jelinek J, et al. A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer. Nucleic Acids Res. 2017;45:8269–81. https://doi.org/10.1093/nar/gkx435.View ArticlePubMedPubMed CentralGoogle Scholar
  24. Li T, Yang D, Li J, Tang Y, Yang J, Le W. Critical role of Tet3 in neural progenitor cell maintenance and terminal differentiation. Mol Neurobiol. 2015;51:142–54. https://doi.org/10.1007/s12035-014-8734-5.View ArticlePubMedGoogle Scholar
  25. Kim R, Sheaffer KL, Choi I, Won KJ, Kaestner KH. Epigenetic regulation of intestinal stem cells by Tet1-mediated DNA hydroxymethylation. Genes Dev. 2016;30:2433–42. https://doi.org/10.1101/gad.288035.116.View ArticlePubMedPubMed CentralGoogle Scholar
  26. Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, et al. Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell. 2011;8:200–13. https://doi.org/10.1016/j.stem.2011.01.008.View ArticlePubMedPubMed CentralGoogle Scholar
  27. Langlois T, daCostaReis M-MB, Lenglet G, Droin N, Marty C, LeCouedic JP, et al. TET2 deficiency inhibits mesoderm and hematopoietic differentiation in human embryonic stem cells. Stem Cells. 2014;32:2084–97. https://doi.org/10.1002/stem.1718.View ArticlePubMedGoogle Scholar
  28. Li J, Wu X, Zhou Y, Lee M, Guo L, Han W, et al. Decoding the dynamic DNA methylation and hydroxymethylation landscapes in endodermal lineage intermediates during pancreatic differentiation of hESC. Nucleic Acids Res. 2018;46:2883–900. https://doi.org/10.1093/nar/gky063.View ArticlePubMedPubMed CentralGoogle Scholar
  29. Iqbal K, Jin SG, Pfeifer GP, Szabo PE. Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc Natl Acad Sci USA. 2011;108:3642–7. https://doi.org/10.1073/pnas.1014033108.View ArticlePubMedGoogle Scholar
  30. Li X, Yue XJ, Pastor WA, Lin LZ, Georges R, Chavez L, et al. Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling. Proc Natl Acad Sci USA. 2016;113:E8267–76. https://doi.org/10.1073/pnas.1617802113.View ArticlePubMedGoogle Scholar
  31. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20:11–24. https://doi.org/10.1016/j.ccr.2011.06.001.View ArticlePubMedPubMed CentralGoogle Scholar
  32. Neri F, Incarnato D, Krepelova A, Dettori D, Rapelli S, Maldotti M, et al. TET1 is controlled by pluripotency-associated factors in ESCs and downmodulated by PRC2 in differentiated cells and tissues. Nucleic Acids Res. 2015;43:6814–26. https://doi.org/10.1093/nar/gkv392.View ArticlePubMedPubMed CentralGoogle Scholar
  33. Serandour AA, Avner S, Oger F, Bizot M, Percevault F, Lucchetti-Miganeh C, et al. Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation-associated enhancers. Nucleic Acids Res. 2012;40:8255–65. https://doi.org/10.1093/nar/gks595.View ArticlePubMedPubMed CentralGoogle Scholar
  34. Hahn MA, Qiu R, Wu X, Li AX, Zhang H, Wang J, et al. Dynamics of 5-hydroxymethylcytosine and chromatin marks in Mammalian neurogenesis. Cell Rep. 2013;3:291–300. https://doi.org/10.1016/j.celrep.2013.01.011.View ArticlePubMedPubMed CentralGoogle Scholar
  35. Tsagaratou A, Aijo T, Lio CW, Yue X, Huang Y, Jacobsen SE, et al. Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation. Proc Natl Acad Sci USA. 2014;111:E3306–15. https://doi.org/10.1073/pnas.1412327111.View ArticlePubMedGoogle Scholar
  36. Nestor CE, Lentini A, Hagg Nilsson C, Gawel DR, Gustafsson M, Mattson L, et al. 5-Hydroxymethylcytosine remodeling precedes lineage specification during differentiation of human CD4(+) T cells. Cell Rep. 2016;16:559–70. https://doi.org/10.1016/j.celrep.2016.05.091.View ArticlePubMedPubMed CentralGoogle Scholar
  37. Taylor SE, Li YH, Smeriglio P, Rath M, Wong WH, Bhutani N. Stable 5-hydroxymethylcytosine (5hmC) acquisition marks gene activation during chondrogenic differentiation. J Bone Miner Res. 2016;31:524–34. https://doi.org/10.1002/jbmr.2711.View ArticlePubMedGoogle Scholar
  38. Ichiyama K, Chen T, Wang X, Yan X, Kim BS, Tanaka S, et al. The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity. 2015;42:613–26. https://doi.org/10.1016/j.immuni.2015.03.005.View ArticlePubMedPubMed CentralGoogle Scholar
  39. Wu H, D’Alessio AC, Ito S, Wang Z, Cui K, Zhao K, et al. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev. 2011;25:679–84. https://doi.org/10.1101/gad.2036011.View ArticlePubMedPubMed CentralGoogle Scholar
  40. Booth MJ, Branco MR, Ficz G, Oxley D, Krueger F, Reik W, et al. Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution. Science. 2012;336:934–7. https://doi.org/10.1126/science.1220671.View ArticlePubMedGoogle Scholar
  41. Pastor WA, Pape UJ, Huang Y, Henderson HR, Lister R, Ko M, et al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature. 2011;473:394–7. https://doi.org/10.1038/nature10102.View ArticlePubMedPubMed CentralGoogle Scholar
  42. Yu M, Hon GC, Szulwach KE, Song CX, Zhang L, Kim A, et al. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell. 2012;149:1368–80. https://doi.org/10.1016/j.cell.2012.04.027.View ArticlePubMedPubMed CentralGoogle Scholar
  43. Tan L, Xiong LJ, Xu WQ, Wu FZ, Huang N, Xu YF, et al. Genome-wide comparison of DNA hydroxymethylation in mouse embryonic stem cells and neural progenitor cells by a new comparative hMeDIP-seq method. Nucleic Acids Res. 2013. https://doi.org/10.1093/nar/gkt091.View ArticlePubMedPubMed CentralGoogle Scholar
  44. Kim M, Park YK, Kang TW, Lee SH, Rhee YH, Park JL, et al. Dynamic changes in DNA methylation and hydroxymethylation when hES cells undergo differentiation toward a neuronal lineage. Hum Mol Genet. 2014;23:657–67. https://doi.org/10.1093/hmg/ddt453.View ArticlePubMedGoogle Scholar
  45. Kriaucionis S, Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in purkinje neurons and the brain. Science. 2009;324:929–30. https://doi.org/10.1126/science.1169786.View ArticlePubMedPubMed CentralGoogle Scholar
  46. Han D, Lu XY, Shih AH, Nie J, You QC, Xu MM, et al. A highly sensitive and robust method for genome-wide 5hmC profiling of rare cell populations. Mol Cell. 2016;63:711–9. https://doi.org/10.1016/j.molcel.2016.06.028.View ArticlePubMedPubMed CentralGoogle Scholar
  47. Colquitt BM, Allen WE, Barnea G, Lomvardas S. Alteration of genic 5-hydroxymethylcytosine patterning in olfactory neurons correlates with changes in gene expression and cell identity. Proc Natl Acad Sci USA. 2013;110:14682–7. https://doi.org/10.1073/pnas.1302759110.View ArticlePubMedGoogle Scholar
  48. Dawlaty MM, Breiling A, Le T, Barrasa MI, Raddatz G, Gao Q, et al. Loss of Tet enzymes compromises proper differentiation of embryonic stem cells. Dev Cell. 2014;29:102–11. https://doi.org/10.1016/j.devcel.2014.03.003.View ArticlePubMedPubMed CentralGoogle Scholar
  49. Lu F, Liu Y, Jiang L, Yamaguchi S, Zhang Y. Role of Tet proteins in enhancer activity and telomere elongation. Genes Dev. 2014;28:2103–19. https://doi.org/10.1101/gad.248005.114.View ArticlePubMedPubMed CentralGoogle Scholar
  50. Hackett JA, Reddington JP, Nestor CE, Dunican DS, Branco MR, Reichmann J, et al. Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline. Development. 2012;139:3623–32. https://doi.org/10.1242/dev.081661.View ArticlePubMedPubMed CentralGoogle Scholar
  51. Liu R, Jin Y, Tang WH, Qin L, Zhang X, Tellides G, et al. Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity. Circulation. 2013;128:2047–57. https://doi.org/10.1161/CIRCULATIONAHA.113.002887.View ArticlePubMedPubMed CentralGoogle Scholar
  52. Zhang R, Cui Q, Murai K, Lim Yen C, Smith Zachary D, Jin S, et al. Tet1 regulates adult hippocampal neurogenesis and cognition. Cell Stem Cell. 2013;13:237–45. https://doi.org/10.1016/j.stem.2013.05.006.View ArticlePubMedPubMed CentralGoogle Scholar
  53. Yang R, Yu T, Kou X, Gao X, Chen C, Liu D, et al. Tet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter. Nat Commun. 2018;9:2143. https://doi.org/10.1038/s41467-018-04464-6.View ArticlePubMedPubMed CentralGoogle Scholar
  54. Kong LC, Tan L, Lv RT, Shi ZN, Xiong LJ, Wu FZ, et al. A primary role of TET proteins in establishment and maintenance of de novo bivalency at CpG islands. Nucleic Acids Res. 2016;44:8682–92. https://doi.org/10.1093/nar/gkw529.View ArticlePubMedPubMed CentralGoogle Scholar
  55. Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315–22. https://doi.org/10.1038/nature08514.View ArticlePubMedPubMed CentralGoogle Scholar
  56. Xie W, Schultz MD, Lister R, Hou Z, Rajagopal N, Ray P, et al. Epigenomic analysis of multiline age differentiation of human embryonic stem cells. Cell. 2013;153:1134–48. https://doi.org/10.1016/j.cell.2013.04.022.View ArticlePubMedPubMed CentralGoogle Scholar
  57. Wu H, D’Alessio AC, Ito S, Xia K, Wang Z, Cui K, et al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature. 2011;473:389–93. https://doi.org/10.1038/nature09934.View ArticlePubMedPubMed CentralGoogle Scholar
  58. Li Y, Zheng H, Wang Q, Zhou C, Wei L, Liu X, et al. Genome-wide analyses reveal a role of Polycomb in promoting hypomethylation of DNA methylation valleys. Genome Biol. 2018;19:18. https://doi.org/10.1186/s13059-018-1390-8.View ArticlePubMedPubMed CentralGoogle Scholar
  59. Neri F, Incarnato D, Krepelova A, Rapelli S, Pagnani A, Zecchina R, et al. Genome-wide analysis identifies a functional association of Tet1 and Polycomb repressive complex 2 in mouse embryonic stem cells. Genome Biol. 2013;14:R91. https://doi.org/10.1186/gb-2013-14-8-r91.View ArticlePubMedPubMed CentralGoogle Scholar
  60. Deplus R, Delatte B, Schwinn MK, Defrance M, Mendez J, Murphy N, et al. TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J. 2013;32:645–55. https://doi.org/10.1038/emboj.2012.357.View ArticlePubMedPubMed CentralGoogle Scholar
  61. Orlanski S, Labi V, Reizel Y, Spiro A, Lichtenstein M, Levin-Klein R, et al. Tissue-specific DNA demethylation is required for proper B-cell differentiation and function. Proc Natl Acad Sci USA. 2016;113:5018–23. https://doi.org/10.1073/pnas.1604365113.View ArticlePubMedGoogle Scholar
  62. Hon GC, Song CX, Du T, Jin F, Selvaraj S, Lee AY, et al. 5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation. Mol Cell. 2014;56:286–97. https://doi.org/10.1016/j.molcel.2014.08.026.View ArticlePubMedPubMed CentralGoogle Scholar
  63. Mahe EA, Madigou T, Serandour AA, Bizot M, Avner S, Chalmel F, et al. Cytosine modifications modulate the chromatin architecture of transcriptional enhancers. Genome Res. 2017;27:947–58. https://doi.org/10.1101/gr.211466.116.View ArticlePubMedPubMed CentralGoogle Scholar
  64. Mellen M, Ayata P, Dewell S, Kriaucionis S, Heintz N. MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell. 2012;151:1417–30. https://doi.org/10.1016/j.cell.2012.11.022.View ArticlePubMedPubMed CentralGoogle Scholar
  65. Hu S, Wan J, Su Y, Song Q, Zeng Y, Nguyen HN, et al. DNA methylation presents distinct binding sites for human transcription factors. Elife. 2013;2:e00726. https://doi.org/10.7554/eLife.00726.View ArticlePubMedPubMed CentralGoogle Scholar
  66. Yang YQA, Zhao JC, Fong KW, Kim J, Li SZ, Song CX, et al. FOXA1 potentiates lineage-specific enhancer activation through modulating TET1 expression and function. Nucleic Acids Res. 2016;44:8153–64. https://doi.org/10.1093/nar/gkw498.View ArticlePubMedPubMed CentralGoogle Scholar
  67. Suzuki T, Shimizu Y, Furuhata E, Maeda S, Kishima M, Nishimura H, et al. RUNX1 regulates site specificity of DNA demethylation by recruitment of DNA demethylation machineries in hematopoietic cells. Blood Adv. 2017;1:1699–711. https://doi.org/10.1182/bloodadvances.2017005710.View ArticlePubMedPubMed CentralGoogle Scholar
  68. Birke M, Schreiner S, Garcia-Cuellar MP, Mahr K, Titgemeyer F, Slany RK. The MT domain of the proto-oncoprotein MLL binds to CpG-containing DNA and discriminates against methylation. Nucleic Acids Res. 2002;30:958–65.View ArticleGoogle Scholar
  69. Bach C, Mueller D, Buhl S, Garcia-Cuellar MP, Slany RK. Alterations of the CxxC domain preclude oncogenic activation of mixed-lineage leukemia 2. Oncogene. 2009;28:815–23. https://doi.org/10.1038/onc.2008.443.View ArticlePubMedGoogle Scholar
  70. Hu DQ, Gao X, Morgan MA, Herz HM, Smith ER, Shilatifard A. The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers. Mol Cell Biol. 2013;33:4745–54. https://doi.org/10.1128/Mcb.01181-13.View ArticlePubMedPubMed CentralGoogle Scholar
  71. Shukla S, Kavak E, Gregory M, Imashimizu M, Shutinoski B, Kashlev M, et al. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature. 2011;479:74–9. https://doi.org/10.1038/nature10442.View ArticlePubMedGoogle Scholar
  72. Marina RJ, Sturgill D, Bailly MA, Thenoz M, Varma G, Prigge MF, et al. TET-catalyzed oxidation of intragenic 5-methylcytosine regulates CTCF-dependent alternative splicing. EMBO J. 2016;35:335–55. https://doi.org/10.15252/embj.201593235.View ArticlePubMedGoogle Scholar
  73. Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466:1129–33. https://doi.org/10.1038/nature09303.View ArticlePubMedPubMed CentralGoogle Scholar
  74. Tsagaratou A, Gonzalez-Avalos E, Rautio S, Scott-Browne JP, Togher S, Pastor WA, et al. TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells. Nat Immunol. 2017;18:45–53. https://doi.org/10.1038/ni.3630.View ArticlePubMedGoogle Scholar
  75. Rudenko A, Dawlaty MM, Seo J, Cheng AW, Meng J, Le T, et al. Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron. 2013;79:1109–22. https://doi.org/10.1016/j.neuron.2013.08.003.View ArticlePubMedPubMed CentralGoogle Scholar
  76. Kumar D, Aggarwal M, Kaas GA, Lewis J, Wang J, Ross DL, et al. Tet1 oxidase regulates neuronal gene transcription, active DNA hydroxy-methylation, object location memory, and threat recognition memory. Neuroepigenetics. 2015;4:12–27. https://doi.org/10.1016/j.nepig.2015.10.002.View ArticlePubMedPubMed CentralGoogle Scholar
  77. Zhu X, Girardo D, Govek EE, John K, Mellen M, Tamayo P, et al. Role of Tet1/3 genes and chromatin remodeling genes in cerebellar circuit formation. Neuron. 2016;89:100–12. https://doi.org/10.1016/j.neuron.2015.11.030.View ArticlePubMedGoogle Scholar
  78. Karuppagounder SS, Kumar A, Shao DS, Zille M, Bourassa MW, Caulfield JT, et al. Metabolism and epigenetics in the nervous system: creating cellular fitness and resistance to neuronal death in neurological conditions via modulation of oxygen-, iron-, and 2-oxoglutarate-dependent dioxygenases. Brain Res. 2015;1628:273–87. https://doi.org/10.1016/j.brainres.2015.07.030.View ArticlePubMedPubMed CentralGoogle Scholar
  79. Zhang J, Chen SQ, Zhang DM, Shi ZX, Li H, Zhao TB, et al. Tet3-mediated DNA demethylation contributes to the direct conversion of fibroblast to functional neuron. Cell Rep. 2016;17:2326–39. https://doi.org/10.1016/j.celrep.2016.10.081.View ArticlePubMedGoogle Scholar
  80. Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood. 2011;118:4509–18. https://doi.org/10.1182/blood-2010-12-325241.View ArticlePubMedPubMed CentralGoogle Scholar
  81. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–301. https://doi.org/10.1056/NEJMoa0810069.View ArticlePubMedGoogle Scholar
  82. Madzo J, Liu H, Rodriguez A, Vasanthakumar A, Sundaravel S, Caces DB, et al. Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis. Cell Rep. 2014;6:231–44. https://doi.org/10.1016/j.celrep.2013.11.044.View ArticlePubMedGoogle Scholar
  83. Yang R, Qu C, Zhou Y, Konkel JE, Shi S, Liu Y, et al. Hydrogen sulfide promotes Tet1- and Tet2-mediated Foxp3 demethylation to drive regulatory T cell differentiation and maintain immune homeostasis. Immunity. 2015;43:251–63. https://doi.org/10.1016/j.immuni.2015.07.017.View ArticlePubMedPubMed CentralGoogle Scholar
  84. Yan HX, Wang YM, Qu XL, Li J, Hale J, Huang YM, et al. Distinct roles for TET family proteins in regulating human erythropoiesis. Blood. 2017;129:2002–12. https://doi.org/10.1182/blood-2016-08-736587.View ArticlePubMedPubMed CentralGoogle Scholar
  85. Montagner S, Leoni C, Emming S, Della Chiara G, Balestrieri C, Barozzi I, et al. TET2 regulates mast cell differentiation and proliferation through catalytic and non-catalytic activities. Cell Rep. 2016;15:1566–79. https://doi.org/10.1016/j.celrep.2016.04.044.View ArticlePubMedPubMed CentralGoogle Scholar
  86. Yue XJ, Trifari S, Aijo T, Tsagaratou A, Pastor WA, Zepeda-Martinez JA, et al. Control of Foxp3 stability through modulation of TET activity. J Exp Med. 2016;213:377–97. https://doi.org/10.1084/jem.20151438.View ArticlePubMedPubMed CentralGoogle Scholar
  87. Kitagawa Y, Ohkura N, Kidani Y, Vandenbon A, Hirota K, Kawakami R, et al. Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat Immunol. 2017;18:173–83. https://doi.org/10.1038/ni.3646.View ArticlePubMedGoogle Scholar
  88. Zhong X, Wang QQ, Li JW, Zhang YM, An XR, Hou J. Ten-eleven translocation-2 (Tet2) is involved in myogenic differentiation of skeletal myoblast cells in vitro. Sci Rep UK. 2017. https://doi.org/10.1038/srep43539.View ArticleGoogle Scholar
  89. Ancey PB, Ecsedi S, Lambert MP, Talukdar FR, Cros MP, Glaise D, et al. TET-catalyzed 5-hydroxymethylation precedes HNF4A promoter choice during differentiation of bipotent liver progenitors. Stem Cell Rep. 2017;9:264–78. https://doi.org/10.1016/j.stemcr.2017.05.023.View ArticleGoogle Scholar
  90. Shimozaki K. Ten-eleven translocation 1 and 2 confer overlapping transcriptional programs for the proliferation of cultured adult neural stem cells. Cell Mol Neurobiol. 2017;37:995–1008. https://doi.org/10.1007/s10571-016-0432-6.View ArticlePubMedGoogle Scholar
  91. Kim H, Jang WY, Kang MC, Jeong J, Choi M, Sung Y, et al. TET1 contributes to neurogenesis onset time during fetal brain development in mice. Biochem Biophys Res Commun. 2016;471:437–43. https://doi.org/10.1016/j.bbrc.2016.02.060.View ArticlePubMedGoogle Scholar
  92. Seritrakul P, Gross JM. Tet-mediated DNA hydroxymethylation regulates retinal neurogenesis by modulating cell-extrinsic signaling pathways. PLoS Genet. 2017;13:e1006987. https://doi.org/10.1371/journal.pgen.1006987.View ArticlePubMedPubMed CentralGoogle Scholar
  93. Mi YJ, Gao XC, Dai JX, Ma Y, Xu LX, Jin WL. A novel function of TET2 in CNS: sustaining neuronal survival. Int J Mol Sci. 2015;16:21846–57. https://doi.org/10.3390/ijms160921846.View ArticlePubMedPubMed CentralGoogle Scholar
  94. Fong KSK, Hufnagel RB, Khadka VS, Corley MJ, Maunakea AK, Fogelgren B, et al. A mutation in the tuft mouse disrupts TET1 activity and alters the expression of genes that are crucial for neural tube closure. Dis Model Mech. 2016;9:585–96. https://doi.org/10.1242/dmm.024109.View ArticlePubMedPubMed CentralGoogle Scholar
  95. Zhao X, Dai J, Ma Y, Mi Y, Cui D, Ju G, et al. Dynamics of ten-eleven translocation hydroxylase family proteins and 5-hydroxymethylcytosine in oligodendrocyte differentiation. Glia. 2014;62:914–26. https://doi.org/10.1002/glia.22649.View ArticlePubMedGoogle Scholar
  96. Rao LJ, Yi BC, Li QM, Xu Q. TET1 knockdown inhibits the odontogenic differentiation potential of human dental pulp cells. Int J Oral Sci. 2016;8:110–6. https://doi.org/10.1038/ijos.2016.4.View ArticlePubMedPubMed CentralGoogle Scholar
  97. Kunimoto H, Fukuchi Y, Sakurai M, Sadahira K, Ikeda Y, Okamoto S, et al. Tet2 disruption leads to enhanced self-renewal and altered differentiation of fetal liver hematopoietic stem cells. Sci Rep. 2012;2:273. https://doi.org/10.1038/srep00273.View ArticlePubMedPubMed CentralGoogle Scholar
  98. Li C, Lan Y, Schwartz-Orbach L, Korol E, Tahiliani M, Evans T, et al. Overlapping requirements for Tet2 and Tet3 in normal development and hematopoietic stem cell emergence. Cell Rep. 2015;12:1133–43. https://doi.org/10.1016/j.celrep.2015.07.025.View ArticlePubMedPubMed CentralGoogle Scholar
  99. Carty SA, Gohil M, Banks LB, Cotton RM, Johnson ME, Stelekati E, et al. The loss of TET2 promotes CD8(+) T cell memory differentiation. J Immunol. 2018;200:82–91. https://doi.org/10.4049/jimmunol.1700559.View ArticlePubMedGoogle Scholar
  100. Chapman CG, Mariani CJ, Wu F, Meckel K, Butun F, Chuang A, et al. TET-catalyzed 5-hydroxymethylcytosine regulates gene expression in differentiating colonocytes and colon cancer. Sci Rep. 2015;5:17568. https://doi.org/10.1038/srep17568.View ArticlePubMedPubMed CentralGoogle Scholar

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