DNA methylation reader MECP2: cell type- and differentiation stage-specific protein distribution
- Congdi Song1,
- Yana Feodorova1,
- Jacky Guy2,
- Leo Peichl3,
- Katharina Laurence Jost4,
- Hiroshi Kimura5,
- Maria Cristina Cardoso4,
- Adrian Bird2,
- Heinrich Leonhardt1,
- Boris Joffe^1 and
- Irina Solovei1Email author
© Song et al.; licensee BioMed Central Ltd. 2014
Received: 22 June 2014
Accepted: 23 July 2014
Published: 3 August 2014
Methyl-CpG binding protein 2 (MECP2) is a protein that specifically binds methylated DNA, thus regulating transcription and chromatin organization. Mutations in the gene have been identified as the principal cause of Rett syndrome, a severe neurological disorder. Although the role of MECP2 has been extensively studied in nervous tissues, still very little is known about its function and cell type specific distribution in other tissues.
Using immunostaining on tissue cryosections, we characterized the distribution of MECP2 in 60 cell types of 16 mouse neuronal and non-neuronal tissues. We show that MECP2 is expressed at a very high level in all retinal neurons except rod photoreceptors. The onset of its expression during retina development coincides with massive synapse formation. In contrast to astroglia, retinal microglial cells lack MECP2, similar to microglia in the brain, cerebellum, and spinal cord. MECP2 is also present in almost all non-neural cell types, with the exception of intestinal epithelial cells, erythropoietic cells, and hair matrix keratinocytes. Our study demonstrates the role of MECP2 as a marker of the differentiated state in all studied cells other than oocytes and spermatogenic cells. MECP2-deficient male (Mecp2-/y) mice show no apparent defects in the morphology and development of the retina. The nuclear architecture of retinal neurons is also unaffected as the degree of chromocenter fusion and the distribution of major histone modifications do not differ between Mecp2-/y and Mecp2 wt mice. Surprisingly, the absence of MECP2 is not compensated by other methyl-CpG binding proteins. On the contrary, their mRNA levels were downregulated in Mecp2-/y mice.
MECP2 is almost universally expressed in all studied cell types with few exceptions, including microglia. MECP2 deficiency does not change the nuclear architecture and epigenetic landscape of retinal cells despite the missing compensatory expression of other methyl-CpG binding proteins. Furthermore, retinal development and morphology are also preserved in Mecp2-null mice. Our study reveals the significance of MECP2 function in cell differentiation and sets the basis for future investigations in this direction.
KeywordsMECP2 MBD Histone modifications Nuclear architecture Mouse retina Retina development Mouse tissues
Methyl-CpG binding protein 2 (MECP2) was discovered as a protein that selectively binds methylated DNA. Mutations of the MECP2 gene were later identified as the principal causative factor for Rett syndrome, a severe progressive neurological disorder affecting almost exclusively females. Mild loss of function mutations, duplications, and expression level alterations has also been found in patients with a plethora of neurological and mental phenotypes[3–6]. In mice, deletion of the Mecp2 gene causes symptoms similar to those of Rett syndrome even when the deletion is restricted to the brain[7–10], while expression of Mecp2 rescues the Rett phenotype. More effective rescue was achieved through embryonic, compared to early postnatal expression[11–13], whereas targeted expression in postmitotic neurons resulted in asymptomatic mice[12, 14]. Mecp2 mutant mice exhibit abnormalities in the number of synapses, the morphology of neuronal processes[16, 17], neuronal maturation, and the neurophysiological activity of these cells[18, 19]. These effects are associated with particular neuron types. For instance, brain stem GABA-ergic neurons are affected, but glycinergic ones are not. Glutamatergic neurons of the brain and their synapses are also affected through the expression level of brain-derived neurotrophic factor (BDNF) which is regulated by MECP2 in a neuronal activity-dependent manner[17, 22, 23].
The results listed above conform to the conclusion that MECP2 deficiency leads to subtle changes in the expression levels of genes causing diverse and widespread phenotypic changes. There is growing evidence that both Mecp2- null astrocytes and microglia affect the dendritic morphology of neurons. Lack of MECP2 causes global histone H3 hyperacetylation in neurons[10, 27], which can have different effects on transcription depending on which lysine residues are acetylated. It remains, however, unknown if global histone H3 acetylation levels increase exclusively in neurons or also take place in glia[10, 21, 27]. Factual data about the phenotypic changes in various tissues of Mecp2- null mice are currently insufficient and partially controversial.
In addition to its role in transcriptional regulation, MECP2 appears to be important for maintenance of the general chromatin organization. Mecp2-null brain shows a ca. 1.6-fold upregulation in spurious transcription of repetitive DNA, in particular L1 retrotransposons and pericentromeric satellites, which have been implicated in maintenance of the nuclear architecture and its formation during cell differentiation[28–30]. In all mouse cells, subcentromeric repetitive blocks, composed of major satellite repeat, form spherical bodies, so called chromocenters that are predominantly located at the nuclear periphery and adjacent to the nucleolus. Remarkably, mouse chromocenters are extremely enriched in MECP2 and the same applies to clusters of human alphoid satellites, also often called chromocenters. There is growing evidence that DNA methylation and MECP2 binding to methylated DNA are pivotal for chromocenter formation and, therefore, the establishment of normal nuclear architecture[31–35]. MECP2 indeed seems to be required for chromocenter fusion during differentiation[8, 32, 36], although other methyl binding (MBD) proteins can compensate for its absence[31, 33, 35].
In order to provide better understanding of MECP2 function, we characterized the distribution of the protein in more than 60 cell types of 16 mouse neuronal and non-neuronal tissues by immunostaining. We show that MECP2 is expressed at a very high level in all retinal neurons except rod photoreceptors. The onset of its expression during retina development coincides with massive formation of the neural synapses. We also describe the distribution of MECP2 in other tissues at various stages of development and relate its increased expression to the terminal differentiation of cells. Mice lacking MECP2 show no apparent defects in the morphology and development of the retina, as well as in the nuclear architecture of retinal neurons. Finally, we show that the absence of MECP2 is not compensated by upregulation of other MBD proteins but rather causes their downregulation.
Results and discussion
We studied mouse tissues because the nuclei of all mouse cells have prominent chromocenters which are convenient for the microscopic approach. The main DNA sequence of chromocenters, major satellite repeat, is present on all autosomes, comprises ca. 10% of whole mouse DNA, contains ca. 50% of the CpG dinucleotides of the whole mouse genome, and was shown to bind MECP2. Therefore, chromocenters can serve as a sensitive indicator of MECP2 expression after immunostaining. To avoid interpretations which might depend only on chromocenters, in all relevant cases, we also studied rat tissues. In contrast to mouse, rat chromosomes do not have large blocks of pericentromeric repeats and therefore do not form noticeable chromocenters in interphase nuclei.
List of antibodies for cell type identification in retina and brain and for recognition of retinal structures
Source, catalogue number
Choline acetyl transferase
Cholinergic amacrine cells
Calcium-binding protein 28 kD
Glial fibrillary acidic protein
Sigma, G 3893
Gamma aminobutyric acid
Amacrine, horizontal cells
Sigma, A 2052
GABA receptor subunit α1
Bipolar, amacrine, and ganglion cell processes in IPL
GABA receptor subunit ρ1
Synapses in IPL
R. Enz, MPI for Brain Research, Frankfurt
Glutamic acid decarboxylase (GABA-synthesizing enzyme)
Amacrine, horizontal cells
Glutamic acid decarboxylase (GABA-synthesizing enzyme)
Amacrine, horizontal cells
Müller cells (astroglia)
BD Biosciences, #610517
Glutamate-gated ion channel (glutamate receptor 3)
Synapses in IPL and OPL
Santa Cruz, sc-7612
Glycine transporter 1
Ionized calcium binding adaptor molecule 1
Microtubule-associated protein 2
NMDA receptor 1 splice variant C2
IPL and OPL synapses
Protein kinase C
Rod bipolar cells
Sigma, P 4334
PKA II β
Human protein kinase A, regulatory subunit II beta
Cone bipolar cells
BD Biosciences, #54720
Postsynaptic density protein 95
Photoreceptors (rods and cones) synapse marker
Membrane of synaptic vesicles
General synapse marker
Dopaminergic amacrine cells
Vesicular glutamate transporter 1
IPL and OPL synapses
Vesicular glutamate transporter 3
Cone bipolar cells
Zebrafish International Resource Center, University of Oregon, Eugene, OR, Znp-1
List of antibodies for cell type identification in tissues other than the retina
Source, catalogue number
Dako, A 0099
Santa Cruz, sc-26630
Santa Cruz, sc-15334
MECP2 in retinal cell types
In contrast to other retinal cells, rod photoreceptor nuclei of nocturnal mammals possess a dramatically different pattern of chromatin distribution. In these cells, a centrally positioned chromocenter is surrounded by a shell of LINE-rich heterochromatin, whereas euchromatin occupies the nuclear periphery. This nuclear organization is inverted in comparison to all other eukaryotic cells possessing conventional nuclear architecture with heterochromatin abutting the nuclear periphery and euchromatin located in the nuclear interior[28, 30]. We have shown that the inverted nuclear architecture in rods has evolved as an adaptation to nocturnal vision: the heterochromatic cores of rod nuclei function as microlenses and reduce light scatter in ONL. Unexpectedly, the nucleoplasm of the inverted rod nuclei is not stained by anti-MECP2 antibodies, and the central chromocenter is only weakly positive (Figure 1A).
In comparison to the multiple chromocenters characteristic of other mouse cell types, the single central chromocenter in mouse rods has a superior chromatin density, which is necessary for rod nuclei to function as microlenses. This high chromatin compaction is obvious from recent electron microscopic studies (e.g., Figure two in and Figure three panel a in) and from the dramatic difference in immunostaining properties between rod chromocenters and chromocenters of other retinal neurons. As described in detail in the recent immunohistochemical studies[38–40], the chromocenter in rods requires much longer antigen retrieval in comparison to the neighboring cones and INL cells. Therefore, to rule out that weak MECP2 staining is caused by inaccessibility of chromocenter chromatin to the antibodies, we made use of transgenic mouse retinas in which rod cells ectopically express lamin B receptor (LBR). Rods expressing transgenic LBR acquire conventional nuclear architecture with euchromatin located to the nuclear interior and heterochromatin, including multiple chromocenters, located at the nuclear periphery. Chromocenters of these transgenic rods have apparently lower chromatin compaction and restore immunostaining ability typical for other retinal cells. However, despite their reduced size and density, chromocenters in LBR-expressing rods remain as weakly MECP2-positive as the chromocenters of wild-type rods (Figure 1B).
The above observations are consistent with results of MECP2 staining in photoreceptors of R7E mice. These transgenic mice specifically express CAG trinucleotide repeat encoding a polyglutamine stretch and represent a mouse model to study spinocerebellar ataxia type 7 (SCA7). In R7E mice, mature rods with inverted nuclei begin to de-differentiate in ca. 1-month-old animals, their nuclei partially restore a conventional nuclear architecture, and photoreceptors lose their rod identity. MECP2 expression in R7E rods gradually increases in parallel to the de-differentiation, and at the age of 20 weeks, the MECP2 level in chromocenters reaches the level observed in the other neurons of the retina (Figure 1C).Furthermore, we also tested for the presence of MECP2 in rods of two other mammalian species: (i) rat, a nocturnal mammal without chromocenters; and (ii) macaque, a diurnal primate with conventional nuclear architecture in rods. In both species, MECP2 was undetectable in rods, in a prominent difference to neuroretinal cells and cone photoreceptors where it produced a clear signal (Figure 1D). Taken together, the above data imply that weak expression of MECP2 is an intrinsic feature of rod photoreceptors.
The low level of MECP2 in rods can be tentatively connected to the relatively high level of linker histone H1c in rod cells described recently for mouse rod photoreceptors. It has been shown that in the MECP2-rich neurons of the brain, approximately half of the linker histone H1 tends to be replaced by MECP2, and that in Mecp2-null mice, the H1 level in these neurons doubles. Remarkably, triple KO mice deficient in linker H1c/H1e/H10 histone variants show significant increase of the rod nuclear diameter which was accompanied by decrease of the nuclear volume occupied by heterochromatin. These changes in the nuclear architecture were noticed only in rod nuclei. The other way around, in de-differentiated rods of R7E mice, which demonstrate significantly reduced level of H1c[44, 45], the expression of MECP2 increases (Figure 1C).
Microglial cells have no detectable MECP2
Retinas of Mecp2-null mice show no apparent defects
List of antibodies for histone modification detection
Source (catalogue number)
Nuclear architecture of neuronal nuclei in Mecp2-null mice is generally preserved
Since MECP2 is a methylation reader and apparently involved in heterochromatin formation[27, 36], we checked whether its absence causes changes in the epigenetic landscape of rod and other retinal nuclei. We found that MECP2 deficiency did not have any microscopically visible effect on the presence and distribution of major histone modifications (Table 3). In Mecp2-/y mice, euchromatin marked by acetylated H3, H4, H3K9ac,me1, and H4K20ac,me1 was present in the nuclear interior of GCL and INL cells and in the outermost peripheral shell of rod nuclei, just as it was observed in WT mice (Figure 3B, Additional file4). The presence of histone modifications H3K9me2,3 and H4K20me2,3, characteristic of heterochromatin, was restricted to the nuclear periphery and chromocenters of neuroretina cells and was also not different from the wild-type (Additional file4; see also).
Conversely, we checked whether erasing of the major heterochromatin hallmarks, H3K9me2,3 and H4K20me3, would prevent MECP2 binding. For this purpose, we studied retinas from mice lacking H4K20me3 due to deletion of Suv4-20 h2 and mice lacking both H4K20me3 and H3K9me3 due to deletion of Suv4-20 and Suv3-9 h1,2 methyltransferases. In mice of both genotypes, rod nuclei had the same morphology as the rod nuclei in the wild-type littermate controls. We found that the pattern of MECP2 staining was not different between the retinal cells in the wild-type and knockout mice, suggesting that MECP2 binding to chromatin was not affected. Indeed, MECP2 was strongly expressed in neuroretina and cones, where it localizes mostly in chromocenters, and was almost undetectable in rods (Additional file5). Recently, it was shown that deletion of Suv4-20 h2 influences chromatin organization in cultured cells, in particular, it increases the number of chromocenters in cultured fibroblasts derived from a Suv3-9/Suv4-20 h double knockout mouse. In contrast, double knockout of Suv3-9 and Suv4-20 affects neither rod nuclear morphology nor MECP2 binding patterns (this study), suggesting that cells in a tissue context might have more redundancy in epigenetic mechanisms than cultured cells.
Although even a complete loss of MECP2 does not prevent chromocenter formation in mouse cells, observations on astroglial cells and neurons differentiated from embryonic stem cells in vitro showed that the number of chromocenters was significantly higher in MECP2-null cells compared to wild-type cells. The other way around, ectopic expression of MECP2 induces clustering and fusion of chromocenters, a process which takes place during myotube differentiation. These findings prompted us to assess rod chromocenter numbers in adult mice of both genotypes. Chromocenter fusion in nuclei of mouse rods is a slow process. A significant proportion of rods at ca. 1 month still have two or more chromocenters; their fusion in all rods is completed only at 2–2.5 months of age ([30, 41]; c.f. Figure 3C2,C3). We scored cells with one and two chromocenters in rod nuclei of Mecp2-/y mice and their wild-type littermates at P30 and P53 (see the ‘Methods’ section for detailed description). The number of rods with two or more chromocenters in Mecp2-/y mice of these ages was 15.5% at P30 and 1.2% at P53, which was not different from the wild-type (Figure 3C1).
In full agreement with our observations on rod cells, data obtained from cortical neurons in tissue sections and primary neuronal cultures indicate that chromocenter number is comparable between neurons from Mecp2-/y and Mecp2+/y mice. Apparently, the difference in results obtained on cells in native tissues of Mecp2-/y and Mecp2+/y mice and on cultured cells derived from these mice is analogous to the observations on Suv3-9/Suv4-20 h double knockout cells and might be tentatively explained by compensatory mechanisms operating in vivo but not in vitro.
Almost all cell types in adult mammalian tissues express MECP2
Involvement of MECP2 in chromatin regulation and maintenance of global nuclear architecture is well documented[27, 52, 53]. In particular, it is known that MECP2 plays a role in the regulation of transcription, being mostly a transcriptional repressor[54–56] and also an activator. In the light of these findings, the fact that some cell types across different species are lacking MECP2 is intriguing and requires further analysis.
Expression of MECP2 increases during tissue development and terminal cell differentiation
The expression of MECP2 in the retina starts at different times depending on the cell type. Remarkably, the onset of expression coincides with massive formation of synapses and, as a consequence, the formation of the IPL and OPL[57–59] (Figure 6A,B). In particular, MECP2 appears in the ganglion and amacrine cells at E17, when a clear gap appears between the GCL and INL + ONL anlage, marking the emerging IPL. Similarly, the MECP2 expression in the bipolar cells starts at P6 together with the formation of the gap between the INL and ONL, which develops into the OPL later. In rods, weak MECP2 expression starts after 2 weeks of postnatal development and remains weak thereafter (Figure 6A,C). Noteworthy, the onset of MECP2 expression roughly correlates with cell birthdays (the day of the last cell division;) of the retinal neuronal cell types (RSpearman = 0.62) and persists afterwards.
Absence of MECP2 is not compensated by altered expression of other MBD proteins in cultured cells and native tissues
Based on the above discussion, the following conclusions were made:
All retinal neurons, except rods, express MECP2 at a high level and the onset of its expression coincides with neuron differentiation, in particular, with massive formation of neural synapses in the inner and outer plexiform layers.
Low expression of MECP2 in rod photoreceptors was found in both the inverted rod nuclei of nocturnal mammals and the conventional rod nuclei of diurnal mammals. We relate this fact to an unusually high level of histone H1c in these cells in comparison to other retinal neurons.
MECP2 is not detectable by immunostaining in the retinal microglial cells, nor in the microglia of the cortex, cerebellum, and spinal cord. In contrast to microglia, the astroglial cells in all neuronal tissues express MECP2 at a level comparable to that in neurons.
The retina of Mecp2-null mice shows no apparent defects in the timing and morphology of the nuclear and plexiform layer formation. No noticeable difference in the distribution of certain neuron types, synapses, and neurotransmitters was found between Mecp2-null and wild-type retinas.
The nuclear architecture of the neuroretinal cells and rod photoreceptors is generally preserved in Mecp2-null mice; in particular, there are no obvious changes in the distribution of pericentromeric heterochromatin and major epigenetic markers characteristic for eu- and heterochromatin.
MECP2 is expressed in the majority of studied 64 non-neuronal cell types; cells which do not express MECP2 are epithelial cells of the intestine, cells of the erythropoietic lineage, hair matrix keratinocytes, and mature gonads; epidermis keratinocytes express MECP2 at a very low level.
Similarly to neurons, the expression of MECP2 in non-neuronal cells is initiated at the late differentiation stages; in this respect, gonads show a reverse pattern with no expression in differentiated oocytes and spermatozoids.
An absence of MECP2 is not compensated by increased expression of other methyl binding proteins; in contrast, expression of some of them was downregulated.
Animals and primary cell cultures
All procedures were approved by the Animal Ethic Committee of Munich University and Edinburgh University. CD1, C57Bl/6, and Mecp2-null mice were killed by cervical dislocation according to the standard protocol. Mecp2 - /y mice (described in; Jackson Laboratory stock number: 003890) were generated along with wild-type littermates by crossing Mecp2 +/- females with wild-type male mice. The generation of mice ectopically expressing LBR in rod cells under the control of the Nrl promoter is described in. Retinas of R7E mice were studied at the age of 70 weeks. Retinas from mice with combined deletions of Suv3-9 and Suv4-20 were a kind gift from G. Schotta (University of Munich). Wild-type littermate controls for all genetically modified mice were studied in parallel. Tail fibroblast cell lines from Mecp2-/y and Mecp2 lox/y mice are described in.
Tissues, fixation, and cryosections
The retinas of the ICR/CD1 mice were studied on each day between E12 and P28. The retinas of Mecp2 - /y mice and their WT littermates were studied at the ages of P1, P7, P14, P30, and P53. Retina fixation, embedding in freezing medium, and preparation of cryosections were performed as described previously[38, 39]. Briefly, the eyes were enucleated immediately after death; the retinas were dissected and fixed with 4% formaldehyde in phosphate-buffered saline (PBS) for various times (15 min, 30 min, 1 h, 3 h, and 24 h). After washing in PBS, the samples were infiltrated in 10%, 20%, and 30% sucrose in PBS before freezing in Jung freezing medium. Importantly, the retina samples at different ages, from WT and transgenic mice, and of various fixation times, were arranged in respective order in the same block to assure identification of all retina samples in a section. Retinas from monkey (Macaca fascicularis) and rat (Rattus norvegicus) were post mortem experimental materials from the MPI for Brain Research (Frankfurt, Germany). Other tissue samples from adult C57Bl/6 mice and rats were fixed with 4% formaldehyde in PBS for 24 h. For some tissues, the samples from different developmental stages – P0, P2, P5, P9, P14, and P28 – were used.
Immunostaining on cryosections
Immunostaining was performed according to the protocol described in detail by[38, 39]. This protocol allows quick testing of a wide range of fixation and antigen retrieval times and detection of the range in which the results of staining are robust. Antigen retrieval was crucial for robust MECP2 staining and was performed by heating cryosections in 10 mM sodium citrate buffer at 80°C. MECP2 detection after 12–24 h of tissue fixation was most successful after 20–30 min of antigen retrieval. For MECP2 immunostaining, mostly rabbit polyclonal antibodies were used. Specificity of the antibody was checked using fibroblasts derived from Mecp2 - /y and Mecp2 lox/y mice (Additional file1). In some cases, rat monoclonal antibodies were used as well. The antibodies for cell type identification and for recognition of retinal structures are listed in Tables 1 and3. Antibodies for the detection of histone modifications are listed in Table 2. Secondary antibodies were anti-mouse IgG conjugated to Alexa555 (A31570, Invitrogen, Renfrew, UK) or Alexa488 (A21202, Invitrogen), and anti-rabbit IgG conjugated to DyLight549 (711-505-152, Jackson ImmunoResearch, West Grove, PA, USA) or DyLight488 (711-485-152, Jackson ImmunoResearch). The nuclei were counterstained with DAPI added to the secondary antibody solution. After staining, the sections were mounted under a coverslip with Vectashield (Vector Laboratories, Inc., Burlingame, CA, USA).
Single optical sections or stacks of optical sections were collected using a Leica TCS SP5 confocal microscope (Milton Keynes, UK) equipped with Plan Apo 63×/1.4 NA oil immersion objective and lasers with excitation lines 405, 488, and 561 nm. Dedicated plug-ins in the ImageJ program were used to compensate for axial chromatic shift between fluorochromes in confocal stacks, to create RGB stacks/images, and to arrange optical sections into galleries[66, 67].
Chromocenters in the rod cells were scored at two age points, P30 and P53. For each age, three mice were used, two Mecp2-/y and one Mecp2 +/y littermate. From each animal 25-μm-thick cryosections were prepared from the three retina areas: central, mid, and peripheral. To distinguish between individual nuclei in tightly packed rod perikarya, the nuclear envelope of rod cells was stained with anti-lamin B1 antibodies (sc-6217). Between 600 and 800 rod cell nuclei were scored in stacks collected from each retina area. Descriptive statistics was performed using SigmaStat software.
RNA isolation and RT-qPCR
List of primers used for real-time PCR
Mbd5 isoform 1**
Brain-derived neurotrophic factor
Ganglion cell layer
Inner nuclear layer
Methyl binding domain
Methyl-CpG binding protein 2
Outer nuclear layer
Outer plexiform layer
Spinocerebellar ataxia type 7
This work was supported by the Deutsche Forschungsgemeinschaft (SO1054/2 to IS, JO903/2 to BJ, SFB 1064/A17 to HL, and CA198/7 to MCC), Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT of Japan (25116005 to HK), and grants from the Rett Syndrome Research Trust and the Wellcome Trust (to AB and JG). The funding bodies had no role in the study design; in the collection, analysis, and interpretation of the data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
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