Open Access

MS_HistoneDB, a manually curated resource for proteomic analysis of human and mouse histones

  • Sara El Kennani1,
  • Annie Adrait1,
  • Alexey K. Shaytan2,
  • Saadi Khochbin3,
  • Christophe Bruley1,
  • Anna R. Panchenko2,
  • David Landsman2,
  • Delphine Pflieger1Email author and
  • Jérôme Govin1Email author
Epigenetics & Chromatin201710:2

DOI: 10.1186/s13072-016-0109-x

Received: 7 October 2016

Accepted: 14 December 2016

Published: 10 January 2017

Abstract

Background

Histones and histone variants are essential components of the nuclear chromatin. While mass spectrometry has opened a large window to their characterization and functional studies, their identification from proteomic data remains challenging. Indeed, the current interpretation of mass spectrometry data relies on public databases which are either not exhaustive (Swiss-Prot) or contain many redundant entries (UniProtKB or NCBI). Currently, no protein database is ideally suited for the analysis of histones and the complex array of mammalian histone variants.

Results

We propose two proteomics-oriented manually curated databases for mouse and human histone variants. We manually curated >1700 gene, transcript and protein entries to produce a non-redundant list of 83 mouse and 85 human histones. These entries were annotated in accordance with the current nomenclature and unified with the “HistoneDB2.0 with Variants” database. This resource is provided in a format that can be directly read by programs used for mass spectrometry data interpretation. In addition, it was used to interpret mass spectrometry data acquired on histones extracted from mouse testis. Several histone variants, which had so far only been inferred by homology or detected at the RNA level, were detected by mass spectrometry, confirming the existence of their protein form.

Conclusions

Mouse and human histone entries were collected from different databases and subsequently curated to produce a non-redundant protein-centric resource, MS_HistoneDB. It is dedicated to the proteomic study of histones in mouse and human and will hopefully facilitate the identification and functional study of histone variants.

Keywords

Histone Histone variants Chromatin Mass spectrometry Proteomics

Background

In eukaryotic cells, the nucleosome is the basic unit of chromatin organization. Nucleosomes are composed of an octamer of four core histones, H2A, H2B, H3 and H4, wrapped by DNA [1]. An additional linker histone, H1, can be deposited near the DNA entry–exit points [2, 3]. The dynamic organization of chromatin impacts many cellular events, including the regulation of gene transcription, DNA replication and the maintenance of genome integrity through DNA repair mechanisms [4, 5]. These pathways signal to chromatin by different mechanisms including DNA methylation, non-coding regulatory RNAs, recruitment of remodelling factors, incorporation of histone variants and covalent modifications of histones [612]. Histones are decorated by many post-translational modifications, the most common of which are acetylation, methylation, phosphorylation and ubiquitination [13, 14]. Some of these modifications favour transcription activation, while others are associated with repression of transcription [15]. In addition to transcription, histone modifications are involved in numerous regulatory circuits, such as chromosome dynamics [16], DNA repair [17] or the establishment and maintenance of heterochromatin [18]. Furthermore, dedicated molecular machineries can load and mobilize nucleosomes along the DNA (for review, see [4]). These chromatin remodellers play an important role in the regulation of transcription by organizing the nucleosomal positions at critical regulatory regions [19, 20]. Finally, non-allelic variants of canonical histones, named histone variants, are important elements in chromatin signalling pathways [21, 22]. Some variants are general players—expressed ubiquitously, contributing to various aspects of transcription and epigenetic regulations—while others are only expressed in certain cell types, such as germ cells [23]. Some of these variants are specifically expressed during sperm differentiation and are annotated TS for testis-specific [2426]. Altogether, histone variants have been described for H3, H2A, H2B and H1; H4 is the only histone for which no variant has been identified in mammals, but some organisms, such as the urochordate Oikopleura dioica, ciliates and trypanosomes, have evolved H4 variants [10, 2729].

Histone variants were initially discovered using classical biochemical approaches. Recently, the development of mass spectrometry (MS) techniques, with constant increases in sensitivity and speed of analysis, has facilitated their identification and functional characterization [14, 3034]. In order to utilize these technologies, histones are first biochemically enriched taking advantage of their highly basic nature. Then, they are proteolyzed with proteases to form short peptides, which are then analysed by MS/MS. The acquired MS/MS spectra are interpreted and converted into amino acid sequences, from which the identity of the original histone protein and the possible presence of post-translational modifications on specific residues can be determined [35]. However, these analyses still remain restricted for a number of reasons. One of these is that the interpretation of MS/MS spectra relies on matching experimental data to theoretical peptide sequences obtained by an in silico proteolysis of a list of proteins. Therefore, the content of the theoretical protein sequence database conditions the interpretation of the experimental spectra and the subsequent identification of histones. Classical databases such as Swiss-Prot, trEMBL and NCBI are usually used with success. However, histones have not been precisely annotated in these resources. Manually curated databases such as Swiss-Prot lack several histones, while others, such as trEMBL or NCBI protein database, are more extensively populated with non-reviewed data. The latter contain more histone entries, but the degree of redundancy and the precision of the descriptions can make protein identification results difficult to interpret. Finally, naming of histones has been recently revisited with a new unified nomenclature [36]. The recent release of HistoneDB 2.0 consolidated the sequence information of a large variety of histones and their sequence variants in many organisms [37]. However, it has not yet been integrated in the above databases and the same variant can go by different names. For instance, the coding gene H2afb1 refers to proteins H2A.L.2 or H2A.Lap3 in the literature and to H2A-Bbd type 1 in the NCBI RefSeq and UniProtKB databases [38, 39]. In addition, a different protein coded by Gm14920 is also named H2A.Bbd.1 in other publications [40]. Here, a unified name is presented to identify uniquely each ambiguous entry and is also associated with its other names to facilitate its relationship with previously published work.

We have collected redundant histone entries from a number of public databases, gathering >700 entries for mouse and >1000 entries for human histones. We manually curated these lists to obtain a final count of 83 and 85 histone entries for mouse or human, respectively. Their annotations have been revisited to match the current histone nomenclature in accordance with the new resource “HistoneDB 2.0—with variants” [37]. About 30% of these entries have a fuzzy UniProtKB protein annotation, such as “predicted” or “inferred by homology”, and we performed MS analysis to clearly identify several of these imprecisely characterized entries (some of which had formerly been described to be detected by western blot).

Results

MS_HistoneDB, a resource containing unique and non-redundant histones

Our initial aim with this work was to generate an exhaustive and non-redundant resource that would facilitate histone analysis by MS. We identified and collected all the information available on human and mouse histones from the public databases of NCBI, Ensembl and UniProtKB (Table 1). This work was aided by the recent release of an updated version of the Histone Database, named “HistoneDB 2.0—with variants” [37]. This database contains 38,664 entries from 1624 species, with 761 and 1039 entries for mouse and human, respectively. In addition, several histones were also considered based on published articles [4145].
Table 1

Histone entries in various publicly accessible databases

 

Mouse

Human

NCBI HistoneDB 2.0

UniProtKB

This study

NCBI HistoneDB 2.0

UniProtKB

This study

H1

170

26

16

126

14

12

H2A

238

44

37

313

44

35

H2B

121

19

16

239

32

21

H3

151

17

13

189

22

16

H4

81

4

1

172

4

1

Total

761

110

83

1039

1126

85

The dataflow is presented in Fig. 1a. This curating process is exemplified with human H2A.Z on Fig. 1b. A total of 23 entries were collected from Swiss-Prot, Uniprot-trEMBL and NCBI databases. Fourteen were duplicated and removed to obtain nine unique entries, which were annotated as H2A.Z.1 and eight spliced isoforms of H2A.Z.2 using the release R86 of the Ensembl database (Fig. 1c, d). In summary, the following rules were applied. First, each entry is protein-centric and therefore defined by the final product, a unique mature protein. Second, it must be associated with gene, transcript and protein accession numbers in NCBI and/or Ensembl, unless published data document its existence. Third, histone names are not always consistent within the existing public databases. Some were renamed following the Talbert et al. nomenclature and in agreement with the HistoneDB 2.0 resource as detailed in the following sections [36, 37]. The final list of histone entries is presented as a phylogenetic tree in Fig. 2 and in Tables 2 and 3 for mouse and human species, respectively. We did not provide here an extensive review of the functional roles of each histone variant, which are already available elsewhere [4, 21, 23, 36, 46].
Fig. 1

Methodology used to create a manually curated MS_HistoneDB resource. a Representation of the dataflow used to generate the MS_HistoneDB resource. b Example of the dataflow for human H2A.Z histone variants. The number of entries at each step is indicated. c Graphical representation of the exons of human H2A.Z.2 spliced isoforms. d Sequence alignment of human H2A.Z variant isoforms

Fig. 2

Phylogenetic trees for mouse and human histone entries in MS_HistoneDB. Please note that for clarity, some putative spliced isoforms of canonical histones were not included, as well as other very short spliced isoforms for some histone variants. The full lists are presented in Tables 2 and 3. Gene names are indicated in italic to identify histone isoforms grouped under a generic term (see Tables 2 and 3; Additional files 4, 5). Black dots highlight testis-specific variants

Table 2

Manually curated list of mouse histones

Histone

Protein name

Entry name for MS analysis

Gene name

UniProtKB

References

H1

H1.1

H1.1

Hist1h1a

P43275

[41, 91]

 

H1.2

H1.2

Hist1h1c

P15864

[41, 92]

 

H1.3

H1.3

Hist1h1d

P43277

[41]

 

H1.4

H1.4

Hist1h1e

P43274

[41]

 

H1.5

H1.5

Hist1h1b

P43276

[41]

 

H1.0 (H1°)

H1.0 (H1°)

H1f0

P10922

[93]

 

TS H1.6 (H1T)

TS H1.6 (H1T)

Hist1h1t

Q07133

[54]

 

TS H1.7 (H1T2, HANP1)

TS H1.7 (H1T2, HANP1)

H1fnt

Q8CJI4

[55, 56]

 

OO H1.8 (H1oo)

OO H1.8.s1 (H1oo)

H1foo

Q8VIK3

[59]

  

OO H1.8.s2

H1foo

Q8VIK3-2

[60]

  

OO H1.8.s3 (putative spliced isoform)

H1foo

E0CZ52

*

  

OO H1.8.s4 (putative spliced isoform)

H1foo

E0CYL2

Short**

  

OO H1.8.s5 (putative spliced isoform)

H1foo

A0A0N4SV54

Short*

 

TS H1.9 (HILS1)

TS H1.9 (HILS1)

Hils1

Q9QYL0

[57, 58]

 

H1.10

H1.10

H1fx

Q80ZM5

*

 

H1.11

H1.11 gene: Gm6970

Gm6970

F7DCP6

*

H2A

Canonical H2A

Canonical H2A genes: Hist1h2ab, Hist1h2ac, Hist1h2ad, Hist1h2ae, Hist1h2ag, Hist1h2ai, Hist1h2an, Hist1h2ao, Hist1h2ap

Hist1h2ab

P22752

[41]

   

Hist1h2ac

P22752

[41]

   

Hist1h2ad

P22752

[41]

   

Hist1h2ae

P22752

[41]

   

Hist1h2ag

P22752

[41]

   

Hist1h2ai

P22752

[41]

   

Hist1h2an

P22752

[41]

   

Hist1h2ao

P22752

[41]

   

Hist1h2ap

P22752

[41]

  

Canonical H2A gene: Hist1h2af

Hist1h2af

Q8CGP5

[41]

  

Canonical H2A gene: Hist1h2ah

Hist1h2ah

Q8CGP6

[41]

  

Canonical H2A gene: Hist1h2ak

Hist1h2ak

Q8CGP7

[41]

  

Canonical H2A gene: Hist1h2al

Hist1h2al

F8WIX8

*

  

Canonical H2A genes: Hist2h2aa1, Hist2h2aa2

Hist2h2aa1

Q6GSS7

[41]

   

Hist2h2aa2

Q6GSS7

[41]

  

Canonical H2A gene: Hist2h2ab

Hist2h2ab

Q64522

[41]

  

Canonical H2A gene: Hist2h2ac

Hist2h2ac

Q64523

[41]

  

Canonical H2A gene: Hist3h2a

Hist3h2a

Q8BFU2

[41]

 

H2A.J (putative variant)

H2A.J.s1 (putative variant)

H2afj

Q8R1M2

*

  

H2A.J.s2 (putative variant, putative spliced isoform)

H2afj

A0A0N4SV66

*

 

H2A.X

H2A.X

H2afx

P27661

[61, 62, 94]

 

H2A.Z.1

H2A.Z.1.s1

H2afz

P0C0S6

[43]

  

H2A.Z.1.s2 (putative spliced isoform)

H2afz

Q3UA95

*

  

H2A.Z.1.s3 (putative spliced isoform)

H2afz

G3UWL7

Short*

  

H2A.Z.1.s4 (putative spliced isoform)

H2afz

G3UX40

Short**

 

H2A.Z.2

H2A.Z.2.s1

H2afv

Q3THW5

[43]

  

H2A.Z.2.s2 (putative spliced isoform)

H2afv

Q8R029

Short*

 

Macro-H2A.1

Macro-H2A.1.s1

H2afy

Q9QZQ8

[95]

  

Macro-H2A.1.s2

H2afy

Q9QZQ8-2

[45]

 

Macro-H2A.2

Macro-H2A.2

H2afy2

Q8CCK0

[96, 97]

 

Macro-H2A.3

Macro-H2A.3 (pseudogene) gene: H2afy3

H2afy3

Q9D3V6

***

 

TS H2A.1

TS H2A.1 (TH2A)

Hist1h2aa

Q8CGP4

[41]

 

H2A.L.1 (H2A.Lap2)

H2A.L.1 (H2A.Lap2) genes: H2al1a, GH2al1c,H2al1d, H2al1f,H2al1g, H2al1h,H2al1i

H2al1a

Q5M8Q2

[38, 39]

   

H2al1c

Q5M8Q2

[38, 39]

   

H2al1d

Q5M8Q2

[38, 39]

   

H2al1f

Q5M8Q2

[38, 39]

   

H2al1g

Q5M8Q2

[38, 39]

   

H2al1h

Q5M8Q2

[38, 39]

   

H2al1i

Q5M8Q2

[38, 39]

  

H2A.L.1 gene: H2al1b

H2al1b

A0A087WP11

*

  

H2A.L.1 gene: H2al1e

H2al1e

Q810S6

*

  

H2A.L.1 gene: H2al1j

H2al1j

A2BFR3

*

  

H2A.L.1 gene: H2al1k

H2al1k

J3QP08

*

  

H2A.L.1 gene: H2al1m

H2al1m

Q9DAD9

*

  

H2A.L.1 gene: H2al1n

H2al1n

Q497L1

*

  

H2A.L.1 gene: H2al1o

H2al1o

L7MU04

*

 

H2A.L.2 (H2A.Lap3, H2A.B.1)

H2A.L.2 (H2A.Lap3, H2A.B.1) gene: H2afb1

H2afb1

Q9CQ70

[38, 39]

 

Y-chr H2A.L.3

Y-chr H2A.L.3 genes: H2al2b, H2al2c

H2al2b

A9Z055

[98]

   

H2al2c

A9Z055

[98]

 

H2A.P (H2A.L3, H2A.Lap4)

H2A.P (H2A.L3, H2A.Lap4) gene: Hypm

Hypm

Q9CR04

[38, 39]

 

H2A.B.2

H2A.B.2 gene: H2afb2

H2afb2

S4R1M3

[40, 99]

 

H2A.B.3

H2A.B.3 gene: H2afb3

H2afb3

S4R1G7

[40, 99]

  

H2A.B.3 (H2A.Lap1) gene: Gm14920

Gm14920

S4R1E0

[39, 40, 99]

H2B

Canonical H2B

Canonical H2B gene: Hist1h2bb

Hist1h2bb

Q64475

[41]

  

Canonical H2B genes: Hist1h2bc, Hist1h2be, Hist1h2bg

Hist1h2bc

Q6ZWY9

[41]

   

Hist1h2be

Q6ZWY9

[41]

   

Hist1h2bg

Q6ZWY9

[41]

  

Canonical H2B genes: Hist1h2bf, Hist1h2bj, Hist1h2bl, Hist1h2bn, Hist1h2bq, Hist1h2br

Hist1h2bf

P10853

[41]

   

Hist1h2bj

P10853

[41]

   

Hist1h2bl

P10853

[41]

   

Hist1h2bn

P10853

[41]

   

Hist1h2bq

P10853

[41]

   

Hist1h2br

P10853

[41]

  

Canonical H2B genes: Hist1h2bq, Hist1h2br (putative spliced isoform)

Hist1h2bq

Q8CBB6

*

   

Hist1h2br

Q8CBB6

*

  

Canonical H2B gene: Hist1h2bh

Hist1h2bh

Q64478

[41]

  

Canonical H2B gene: Hist1h2bk

Hist1h2bk

Q8CGP1

[41]

  

Canonical H2B gene: Hist1h2bm

Hist1h2bm

P10854

[41]

  

Canonical H2B gene: Hist1h2bp Spliced isoform 1 (main)

Hist1h2bp

Q8CGP2

[41]

  

Canonical H2B gene: hist1h2bp (putative spliced isoform)

Hist1h2bp

Q8CGP2-2

[41]

  

Canonical H2B gene: Hist2h2bb

Hist2h2bb

Q64525

[41]

  

Canonical H2B gene: Hist2h2be

Hist2h2be

Q64524

[41]

  

Canonical H2B gene: Hist3h2ba

Hist3h2ba

Q9D2U9

[41]

  

Canonical H2B gene: Hist3h2bb

Hist3h2bb

Q8CGP0

*

 

TS H2B.1 (TH2B)

TS H2B.1 (TH2B)

Hist1h2ba

P70696

[41, 79]

 

subH2B (H2BL.1)

subH2B (H2BL.1)

1700024p04rik

Q9D9Z7

[38, 100]

 

H2B.L.2

H2B.L.2

H2bfm

Q9DAB5

[38]

H3

Canonical H3.1

Canonical H3.1

Hist1h3a

P68433

[41]

   

Hist1h3g

P68433

[41]

   

Hist1h3h

P68433

[41]

   

Hist1h3i

P68433

[41]

 

Canonical H3.2

Canonical H3.2

Hist1h3b

P84228

[41]

   

Hist1h3c

P84228

[41]

   

Hist1h3d

P84228

[41]

   

Hist1h3e

P84228

[41]

   

Hist1h3f

P84228

[41]

   

Hist2h3b

P84228

[41]

   

Hist2h3c1

P84228

[41]

   

Hist2h3c2

P84228

[41]

 

H3.3

H3.3 genes: H3f3a, H3f3b

H3f3a

P84244

[101, 102]

   

H3f3b

P84244

[101, 102]

  

H3.3 gene: Gm6421

Gm6421

EDL18362.1

[103]

  

H3.3 gene: Gm10257

Gm10257

XP_003084990.1

[103]

 

cenH3-CENPA

cenH3-CENPA.s1

Cenpa

O35216

[104]

  

cenH3-CENPA.s2 (putative spliced isoform)

Cenpa

D6RCV6

Short**

  

cenH3-CENPA.s3 (putative spliced isoform)

Cenpa

D6RJ71

**

  

cenH3-CENPA.s4 (putative spliced isoform)

Cenpa

A0A0G2JEV0

*

  

cenH3-CENPA.s5 (putative spliced isoform)

Cenpa

A0A0G2JGI2

*

  

cenH3-CENPA.s6 (putative spliced isoform)

Cenpa

A0A0G2JEV2

**

 

H3.5

H3.5

H3f3c

P02301

***

 

TS H3.4 (H3T)

TS H3.4 (H3T)

Gm12260

NP_001304932.1

[74]

H4

H4

H4

Hist1h4a

P62806

[41, 105]

   

Hist1h4b

P62806

[41, 105]

   

Hist1h4c

P62806

[41, 105]

   

Hist1h4d

P62806

[41, 105]

   

Hist1h4f

P62806

[41, 105]

   

Hist1h4h

P62806

[41, 105]

   

Hist1h4i

P62806

[41, 105]

   

Hist1h4j

P62806

[41, 105]

   

Hist1h4k

P62806

[41, 105]

   

Hist1h4m

P62806

[41, 105]

   

Hist1h4n

P62806

[41, 105]

   

Hist2h4

P62806

[41, 105]

   

Hist4h4

P62806

[41, 105]

Their protein names have been adapted to improve their identification and analysis by mass spectrometry. Indeed, the column “Entry name for MS analysis” represents the information present in the FASTA file (Additional file 1) used as a database to identify peptides and proteins after an MS analysis. The last column indicates studies on histones that described evidence of transcript and/or protein existence. For the sake of completeness, histone entries lacking a related publication were retained and the classification currently proposed by the Ensembl database was specified, as follows

* “Protein coding”, genes and/or transcript that contains an open reading frame (ORF)

** “Nonsense mediated decay”, transcript is thought to undergo nonsense mediated decay

*** “Pseudogene”, genes containing frameshift and/or stop codon(s) that disrupt the ORF

The term “Short” indicates that the putative protein is significantly smaller than conventional histones; its incorporation into chromatin and its biological function is then doubtful. Additional file 4 presents links to gene, transcripts and protein entries to Ensembl and UniProtKB databases

Table 3

Manually curated list of human histones

Histone

Protein name

Entry name for MS analysis

Gene name

UniProtKB Accession

References

H1

H1.1

H1.1

Hist1h1a

Q02539

[41, 106, 107]

H1.2

H1.2

Hist1h1c

P16403

[41, 106, 107]

H1.3

H1.3

Hist1h1d

P16402

[41, 106, 107]

H1.4

H1.4

Hist1h1e

P10412

[41]

H1.5

H1.5

Hist1h1b

P16401

[41, 108]

H1.0 (H1°)

H1.0 (H1°)

H1f0

P07305

[109]

TS H1.6 (H1t)

TS H1.6 (H1t)

Hist1h1t

P22492

[41]

TS H1.7 (H1T2, HANP1)

TS H1.7 (H1T2, HANP1)

H1fnt

Q75WM6

[110]

OO H1.8 (H1oo)

OO H1.8.s1 (H1oo)

H1foo

Q8IZA3-1

[111, 112]

OO H1.8.s2 (putative spliced isoform)

H1foo

Q8IZA3-2

*

TS H1.9 (Hils)

TS H1.9 (Hils)

Hils1

P60008

[57]

H1.10

H1.10

H1fx

Q92522

[113]

H2A

Canonical H2A

Canonical H2A genes: Hist1h2ag, Hist1h2ai, Hist1h2ak, Hist1h2al, Hist1h2am

Hist1h2ag

P0C0S8

[41]

Hist1h2ai

P0C0S8

[41]

Hist1h2ak

P0C0S8

[41]

Hist1h2al

P0C0S8

[41]

Hist1h2am

P0C0S8

[41]

Canonical H2A gene: Hist1h2ac

Hist1h2ac

Q93077

[41]

Canonical H2A gene: Hist1h2ad

Hist1h2ad

P20671

[41]

Canonical H2A gene: Hist1h2ae

Hist1h2ae

P04908

[41]

Canonical H2A gene: Hist1h2ah

Hist1h2ah

Q96KK5

[41]

Canonical H2A gene: Hist1h2aj

Hist1h2aj

Q99878

[41]

Canonical H2A gene:Hist2h2aa4

Hist1h2aa4

Q6FI13

[41]

Canonical H2A gene: Hist2h2ab

Hist2h2ab

Q8IUE6

[41]

Canonical H2A gene: Hist2h2ac

Hist2h2ac

Q16777

[41]

Canonical H2A gene: Hist3h2a

Hist3h2a

Q7L7L0

[41]

Canonical H2A (pseudogene)

Hist1h2Aps4

Q92646

***

H2A.J (putative variant)

H2A.J.s1

H2afj

Q9BTM1-1

**

H2A.J.s2 (putative spliced isoform)

H2afj

Q9BTM1-2

**

H2A.J.s3 (putative spliced isoform)

H2afj

H0YFX9

Short**

H2A.X

H2A.X

H2afx

P16104

[61, 114]

H2A.Z.1

H2A.Z.1

H2afz

P0C0S5

[115, 116]

H2A.Z.2

H2A.Z.2.s1

H2afv

Q71UI9-1

[116]

H2A.Z.2.s2

H2afv

Q71UI9-2

[65]

H2A.Z.2.s3 (putative spliced isoform)

H2afv

Q71UI9-4

[65]

H2A.Z.2.s4 (putative spliced isoform)

H2afv

Q71UI9-5

[65]

H2A.Z.2.s5 (putative spliced isoform)

H2afv

Q71UI9-3

[65]

H2A.Z.2.s6 (putative spliced isoform)

H2afv

C9J0D1

*

H2A.Z.2.s7 (putative spliced isoform)

H2afv

C9J386

Short*

H2A.Z.2.s8 (putative spliced isoform)

H2afv

E5RJU1

Short*

macroH2A.1

macroH2A.1.s1

H2afy

O75367

[117]

macroH2A.1.s2

H2afy

O75367-2

[66]

macroH2A.1.s3 (putative spliced isoform)

H2afy

B4DJC3

*

macroH2A.1.s4 (putative spliced isoform)

H2afy

D6RCF2

***

macroH2A.1.s5 (putative spliced isoform)

H2afy

O75367-3

*

macroH2A.2

macroH2A.2.s1

H2afy2

Q9P0M6

[96, 97]

macroH2A.2.s2 (putative spliced isoform)

H2afy2

Q5SQT3

*

TS H2A.1 (TH2A)

TS H2A.1 (TH2A)

Hist1h2aa

Q96QV6

[71]

H2A.B.1

H2A.B.1

H2afb1

P0C5Y9

[118, 119]

H2A.B.2

H2A.B.2

H2afb2

P0C5Z0

*

H2afb3

H2A.P

H2A.P

Hypm

O75409

*

H2B

Canonical H2B

Canonical H2B gene: Hist1h2bb

Hist1h2bb

P33778

[41]

Canonical H2B genes: Hist1h2bc, Hist1h2be, Hist1h2bf, Hist1h2bg, Hist1h2bi

Hist1h2bc

P62807

[41]

Hist1h2be

P62807

[41]

Hist1h2bf

P62807

[41]

Hist1h2bg

P62807

[41]

Hist1h2bi

P62807

[41]

Canonical H2B gene: Hist1h2bd

Hist1h2bd

P58876

[41]

Canonical H2B gene: Hist1h2bh

Hist1h2bh

Q93079

[41]

Canonical H2B gene: Hist1h2bj

Hist1h2bj

P06899

[41]

Canonical H2B gene: Hist1h2bj (putative spliced isoform)

Hist1h2bj

U3KPT8

*

Canonical H2B gene: Hist1h2bk

Hist1h2bk

O60814

[41]

Canonical H2B gene: Hist1h2bl

Hist1h2bl

Q99880

[41]

Canonical H2B gene: Hist1h2bm

Hist1h2bm

Q99879

[41]

Canonical H2B gene: Hist1h2bn

Hist1h2bn

Q99877

[41]

Canonical H2B gene: Hist1h2bn (putative spliced isoform)

Hist1h2bn

U3KQK0

[41]

Canonical H2B gene: Hist1h2bo

Hist1h2bo

P23527

[41]

Canonical H2B gene: Hist2h2be

Hist2h2be

Q16778

[41]

Canonical H2B gene: Hist2h2bf (putative spliced isoform)

Hist2h2bf

Q5QNW6

*

Canonical H2B gene: Hist2h2bf (putative spliced isoform)

Hist2h2bf

Q5QNW6-2

*

Canonical H2B gene: Hist3h2bb

Hist3h2bb

Q8N257

[41]

H2B.S (putative variant)

H2B.S (putative variant)

H2bfs

P57053

*

H2B.M (putative variant)

H2B.M.s1 (putative variant)

H2bfm

P0C1H6

*

H2B.M.s2 (putative variant, putative spliced isoform)

H2bfm

A9UJN3

Short*

H2B.W

H2B.W

H2bfwt

Q7Z2G1

[72, 120, 121]

TS H2B.1 (TH2B)

TS H2B.1 (TH2B)

Hist1h2ba

Q96A08

[41, 71]

H3

Canonical H3.1

Canonical H3.1 genes: Hist1h3a, Hist1h3b, Hist1h3c, Hist1h3d, Hist1h3e, Hist1h3f, Hist1h3g, Hist1h3h, Hist1h3i, Hist1h3j

Hist1h3a

P68431

[41]

Hist1h3b

P68431

[41]

Hist1h3c

P68431

[41]

Hist1h3d

P68431

[41]

Hist1h3e

P68431

[41]

Hist1h3f

P68431

[41]

Hist1h3g

P68431

[41]

Hist1h3h

P68431

[41]

Hist1h3i

P68431

[41]

Hist1h3j

P68431

[41]

Canonical H3.2

Canonical H3.2 genes: Hist2h3a, Hist2h3c, Hist2h3d

Hist2h3a

Q71DI3

[41]

Hist2h3c

Q71DI3

[41]

Hist2h3d

Q71DI3

[41]

Canonical H3.2 (pseudogene)

Hist2h3ps2

Q5TEC6

*

H3.3

H3.3.s1

H3f3a

P84243

[122, 123]

H3f3b

P84243

[122, 123]

H3.3.s2 (putative spliced isoform)

H3f3a

B4DEB1

*

H3f3b

B4DEB1

*

H3.3.s3 (putative spliced isoform)

H3f3b

K7EK07

*

H3.3.s4 (putative spliced isoform)

H3f3b

K7EMV3

*

H3.3.s5 (putative spliced isoform)

H3f3b

K7EP01

*

H3.3.s6 (putative spliced isoform)

H3f3b

K7ES00

*

H3.Y.1

H3.Y.1

H3.Y

Translated from NG_012784.2

[44]

H3.Y.2 (H3.X)

H3.Y.2 (H3.X)

H3.X

Translated from NG_023411.2

[44]

H3.5

H3.5

H3f3c

Q6NXT2

[75]

cenH3-CENPA

cenH3 - CENPA

Cenpa

P49450-1

[124]

cenH3.s1 (putative spliced isoform)

Cenpa

P49450-2

*

cenH3.s2 (putative spliced isoform)

Cenpa

F8WD88

Short**

TS H3.4 (H3t)

TS H3.4 (H3t)

Hist3h3

Q16695

[41]

H4

H4

H4

Hist1h4a

P62805

[41]

Hist1h4b

P62805

[41]

Hist1h4c

P62805

[41]

Hist1h4d

P62805

[41]

Hist1h4e

P62805

[41]

Hist1h4f

P62805

[41]

Hist1h4h

P62805

[41]

Hist1h4i

P62805

[41]

Hist1h4j

P62805

[41]

Hist1h4k

P62805

[41]

Hist1h4l

P62805

[41]

Hist2h4a

P62805

[41]

Hist2h4b

P62805

[41]

Hist4h4

P62805

[41]

Please refer to the Table 2 for legend. The corresponding FASTA file is presented as Additional file 2. Additional file 5 presents links to gene, transcripts and protein entries to Ensembl and UniProtKB databases

Canonical histones

Canonical histones constitute the bulk of the proteins that organize DNA into chromatin. They are synthesized and incorporated into chromatin during replication [41]. Their expression is carefully regulated to provide enough proteins to be loaded onto newly synthesized DNA while preventing the accumulation of free histones [47, 48]. For this reason, they are denominated “replication-dependent” and their mRNA adopts a unique organization (for review, see [49]). They are the only RNA polymerase II transcripts which are not polyadenylated but instead possess a 3′ stem-loop, formed during the maturation of their mRNA and which is essential for their regulation [49]. However, polyadenylation events of replication-dependent histone mRNA have recently been identified in terminally differentiated cells and suggested to provide a replacement pool of canonical histones [50].

H2A and H2B canonical histones have minor sequence variations, and it is not clear yet whether these have a functional significance [51]. MS analysis can differentiate between these isoforms and their denomination had to be adapted for proteomic analysis. Here, we propose that canonical H2A and H2B isoforms can be regrouped under the generic term “canonical H2A” or “canonical H2B”, complemented by the gene name of each isoform (Tables 2, 3).

Histone variants are mostly replication-independent

In contrast to canonical histones, almost all histone variants are synthesized independently of the cell cycle and named “replication-independent” [49]. Their mRNA is polyadenylated and these histones are incorporated into chromatin at any time of the cell cycle. Two exceptions are the testis-specific (TS) histone variants TS H2A and TS H2B, which possess a 3′ stem-loop in their mRNA. For this reason, they have been classified as replication-dependent [49] even if expressed in differentiating germ cells which replicate their DNA only once before meiosis.

Spliced and putative isoforms

More than 40 spliced isoforms for all mouse and human histones are present in the Ensembl database. However, this information, mainly based on transcriptional data, remains questionable; notably whether the corresponding proteins are expressed and incorporated into chromatin is uncertain. Some spliced isoforms correspond to very short isoforms that lack the globular domain and are probably, if expressed, non-functional (mouse: cenH3-CENPA.s2, cenH3-CENPA.s3, cenH3-CENPA.s4, cenH3-CENPA.s5, OO H1.8.s.4, OO H1.8.s.5, H2A.Z.1.s3, H2A.Z.1.s4, H2A.Z.2.s2; human: H2A.J.s3, H2A.Z.2.s7, H2A.Z.2.s8, canonical H2B.s2, cenH3-CENPA.s2). Even though their expression remains highly uncertain, they have been included in MS_HistoneDB for their identification by MS to be possible. Observing the presence of a shorter non-functional sequence at the expense of the full-length histone would indeed constitute interesting information. Following the same rationale, several putative isoforms or pseudogenes have been included in this resource (Tables 2, 3). Their detection by MS will constitute an indispensable step to confirm the expression of their protein form.

H1 histones

H1 histones (or linker histones) are different from core histones with respect to their structure, function and evolution. Therefore, it is not possible to single out one of its isoforms as canonical. H1 variants are known to encompass isoforms named H1.0–H1.10. H1.1–H1.5 from histone gene cluster 1 and orphan genes H1.0 (H1°) and H1.10 are usually referred to as somatic variants [36]. The linker variant H1.0 has been described to be involved in cell differentiation (for review [2, 52]). H1.10 has been identified in human and plays an essential role for mitotic progression [53]. H1 variants also include the TS proteins TS H1.6 [54], TS H1.7 [55, 56], TS H1.9 [57, 58] and the oocyte-specific OO H1.8 variant [59, 60]. Finally, a new mouse entry, H1.11, was identified here while performing an in silico search using sequence alignments.

H2A variants

H2A variants comprise H2A.X, H2A.Z, macro-H2A and a number of TS variants, TS H2A, H2A.L/H2A.P and H2A.B.

Only one H2A.X protein has been described; this variant is involved in double-strand break repair, genome stability and chromatin remodelling and silencing in male meiosis [6164]. H2A.Z is involved in transcription regulation and is encoded by two different genes, H2afz and H2afv [43]. In mouse, four putative spliced isoforms may be expected in addition to the two original sequences, while in human eight H2A.Z.2 isoforms have been suggested, of which two have been demonstrated to be stable at the protein level [65]. The specific functional roles of these isoforms are not well understood yet, but in some specific tissues, such as in the brain, some H2A.Z spliced isoforms could provide context-specific signalling information [65].

Macro-H2A is the largest histone variant with a long C-terminal domain [66]. This histone variant is associated with transcription repression, although recent evidence suggests that in some conditions it may also promote transcription (reviewed in [51]). Macro-H2A is known to be encoded by two or three different genes, for human and mouse, respectively, some of which are differentially spliced. These variable forms allow differential binding of NAD [67].

Finally, many H2A variants are specifically expressed in the testis. First, TS H2A.1 was originally identified in 1982 in the testis, where it plays an important role and was later detected in the ovary [41, 6871].

Fourteen other mouse TS H2A variants have been grouped into three main classes, H2A.L, H2A.B and H2A.P (Fig. 3). This class also regroups human variants, with two H2A.B and one H2A.P proteins (Fig. 3). They are involved in transcription regulation and the final chromatin reorganization during post-meiotic differentiation of sperm cells [26, 38, 39]. The mouse variants have been described by different research groups [38, 39], and a denomination used here follows previous publications [36, 37]. When potential protein products of different genes have only minor sequence variations and no functional difference has been characterized, we grouped them under the name with the same number suffix (e.g. H2A.L.1); however, the gene name is provided in the name of the entry as the second qualifier. Future studies might warrant splitting of such groups of proteins if functional differences between the members are detected. Currently, H2A.B.2 and H2A.B.3 are proposed to be numbered following their gene name, i.e. H2AFB2 and H2AFB3, respectively. In 2007, new TS H2A variants were identified and named H2AL1 and H2AL2. [38]. A few years later, these histones were independently identified and named H2A.Lap2 and H2A.Lap3, respectively [39]. This latter work also reported the identification and functional characterization of a third member baptized H2A.Lap1 which falls into H2A.B group and is proposed to be regrouped with the highly similar protein H2A.B.3. H2A.L.3 was originally identified by S. Khochbin’s group [38] and is the same as H2A.Lap4, also identified by D. Tremethick’s group [39]. However, it forms a separate phylogenetic clade in placental mammals and is named H2A.P here according to [36].
Fig. 3

Phylogenetic tree of the mouse and human H2A.L, H2A.B and H2A.P histone variants

H2B variants

Variants TS H2B.1, H2B.L and H2B.W were first identified as TS. In the testes, these proteins are involved in the chromatin-to-protamine transition [38, 69, 72, 73]. Then, TS H2B.1 and TS H2A.1 were also identified in human oocytes, where they favour the generation of induced pluripotent cells [70, 71]. In human, some genes (e.g. H2BFM, H2BFS) still await characterization and have been denoted as putative variants in this work (Table 3).

H3 variants

H3 has several isoforms: H3.1 and H3.2 are replication-dependent; H3.3 is considered to be a replication-independent histone variant, while TS H3.4 and H3.5 are TS [74, 75]. Several new isoforms of H3.3 were included in the database developed here along with two other human H3 histone variants, H3.X and H3.Y [44].

CenH3/CENPA is a well-known centromeric H3 variant with many spliced isoforms. Its name has been the subject of heated discussion, which is out of the scope of our work [36, 76, 77]. We therefore propose to use both names, cenH3-CENPA, until a consensus has been reached by the community.

Generation of MS-based databases

De novo MS data interpretation methods are naive and do not rely on pre-existing databases. However, MS data acquired on histones are generally matched to a database containing all the protein sequences that could theoretically be found in the sample. Using this approach, a given histone protein cannot be identified if its sequence is not present in the database explored by the MS/MS data interpretation software. We used MS_HistoneDB to create a new search space dedicated to the analysis of histones. Basically, mouse or human non-redundant and well-annotated Swiss-Prot FASTA files were cleared of their histone sequences and then repopulated using MS_HistoneDB. This resource is included as Additional files 1 and 2, providing resources to study histones in mouse and human samples, respectively.

Identification of new histones in mouse

About 30% of the proteins in MS_HistoneDB have imprecise protein annotations in UniProtKB and are presented in Tables 4 and 5. These tables regroup histones that are annotated in the UniProtKB and NCBI databases as “inferred from homology” or “predicted”. Even though a certain number of these histones have already been described in publications, which provide clear evidence of their existence at mRNA and protein levels, they may not have been identified by MS yet. This could explain their poor annotation status in UniProtKB.
Table 4

Mouse histone variants with poor annotation status in the UniProtKB database

Names

Accession number

Protein status

Method of detection

References

This study (number of identified peptides)

Other MS-based studies

Not MS-based studies

H1.0 (H1°)

P10922

Transcript

Yes (5)

Yes

RT-PCR; WB

[128]

TS H1.7 (H1T2, HANP1)

Q8CJI4

Transcript

Yes (6)

 

NB; WB

[55]

OO H1.8 (H1oo)

Q8VIK3

Transcript

  

WB

[59, 60, 129]

H1.11

F7DCP6

Inferred

    

Macro-H2A.3

Q9D3V6

Transcript

    

H2A.L.1 gene: H2al1b

A0A087WP11

Inferred

Yes (1)

   

H2A.L.1 gene: H2al1j

A2BFR3

Inferred

    

H2A.L.1 gene: H2al1 k

J3QP08

Inferred

    

H2A.L.1 gene: H2al1 m

Q9DAD9

Transcript

    

H2A.L.1 gene: H2al1n

Q497L1

Transcript

Yes (2)

   

H2A.L.1 gene: H2al1o

L7MU04

Inferred

    

H2A.L.2 (H2A.B1,H2A.Lap3)

Q9CQ70

Transcript

Yes (3)

Yes

RT-PCR; NB; WB

[38, 39, 125]

Y-chr H2A.L.3

A9Z055

Transcript

  

RT-PCR

[98]

H2A.P (H2A.L3,H2A.Lap4,)

Q9CR04

Inferred

  

RT-PCR

[38, 39]

H2A.B.2

S4R1M3

Inferred

  

RT-PCR; WB

[40, 99]

H2A.B.3 gene: H2afb3

S4R1G7

Inferred

  

RT-PCR; WB

[40, 99]

H2A.B.3 (H2A.Lap1) gene: GM14920

S4R1E0

Inferred

  

RT-PCR; WB

[39, 40, 99]

H2B.L.2

Q9DAB5

Transcript

Yes (4)

Yes

RT-PCR; WB

[38]

H3.3 gene: GM6421

EDL18362.1

Predicted

Yes (1)

Yes

RT-PCR

[103]

H3.3 gene: GM10257

XP_003084990.1

Record removed

Yes (1)

 

RT-PCR

[103]

CENPA-cenH3

O35216

Transcript

 

Yes

qPCR; WB

[126, 127]

H3.5

P02301

Inferred

  

RT-PCR

 

TS H3.4 (H3t)

NP_001304932.1

Predicted

 

Yes

RT-PCR

[103]

The “protein status” was retrieved from UniProtKB: “Evidence at transcript level” (noted “Transcript”) or “Inferred from homology” (noted “Inferred”, update of July 2016). Three variants are predicted in NCBI database and are absent in UniProtKB. Information about the detection of some variants at the mRNA level (e.g. by RT-PCR) or at the protein level (e.g. by WB or MS) was further completed with publications and compared to the MS identification results obtained in the present study

NB northern blot, WB western blot, MS mass spectrometry

Table 5

Human histone variants with poor annotation status in the UniProtKB database

Name (other names)

Protein status

Accession number

Method of detection

References

TS H1.6 (H1t)

Transcript

P22492

WB

[41]

TS H1.7 (H1T2, HANP1)

Transcript

Q75WM6

NB; WB

[110]

OO H1.8 (H1oo)

Transcript

Q8IZA3-1

RT-PCR

[111, 112]

H2A.1.ps

Inferred

Q92646

  

H2A.B.1 (H2A.Bbd)

Transcript

P0C5Y9

WB

[118, 119, 130]

H2A.B.2 (H2A.Bbd)

Transcript

P0C5Z0

WB

[118, 119, 130]

The “protein status” was retrieved from UniProtKB: “Evidence at transcript level” (noted “Transcript”) or “Inferred from homology” (noted “Inferred”, update of July 2016). Information about the detection of some variants at the mRNA level (e.g. by RT-PCR) or at the protein level (e.g. by WB or MS) was further completed with publications

NB northern blot, WB western blot, MS mass spectrometry

At the RNA level, almost all histone variants have been detected in the testis [3840, 55, 57, 68, 7881]. Moreover, the expression profile of the mouse H2A.L.1 isoforms which are described in this study has been explored. RNA-seq data from nine mouse tissues have been obtained from a recently published dataset [82]. Expression data were available for 7 out of the 8 H2A.L.1 mouse histone entries and confirm that all of them are mainly expressed in the testis, similarly to H2A.L.2 and H2A.P (Fig. 4a) [38, 39]. Gene expression profiles during spermatogenesis have been obtained from Ref. [83]. It also confirms that H2A.L.1 isoforms are expressed in the post-meiotic stage in spermatids, similarly to H2A.L.2 and H2A.P (Figs. 3c, 4b) [38, 39].
Fig. 4

Mouse H2A.L, H2A.B and H2A.P isoforms are expressed in the post-meiotic stages of spermatogenesis. a Expression profile of a selection of H2A.L, H2A.B and H2A.P genes across mouse tissues. All of them are testis-specific. Data were extracted using gene names provided in Table 2 and Additional file 4 from a dataset downloaded from Expression Atlas [87] and published in Ref. [82]. b Expression profiles of a selection of H2A.L, H2A.B and H2A.P genes during mouse spermatogenesis, revealing a maximum expression in the post-meiotic stage. Data have been obtained from Ref. [83]. Lepto leptotene, Zygo zygotene. c Coomassie-stained SDS-PAGE gel loaded with histones extracted from whole testis and elongating spermatids. d Peptides of the mouse H2A.L histone variants identified by mass spectrometry analysis (identified peptides are highlighted in red boxes)

We next decided to test whether MS_HistoneDB would allow the identification by MS of histone entries with imprecise protein annotation using mouse testis. Histones were purified from whole testis or from elongating spermatids (Fig. 4c). Mass spectrometry analysis combined with MS_HistoneDB allowed identification of nine of these poorly annotated proteins (Table 4; Additional file 3). Each newly MS-identified variant was detected by 1–10 specific peptide sequences. The current guidelines for the identification of previously undetected human proteins (“missing proteins”) require the identification of two different peptide sequences of at least nine amino acids in length [84]. To stringently apply the same rules to validate new histone variants would be demanding, given the very high level of sequence homology between some variants. However, out of the nine histone variants detected here for the first time at the protein level by MS-based approaches, six were identified with at least two non-overlapping peptides of length ≥9 amino acids. Almost all the newly identified variants are TS. This analysis thus confirmed the existence of H2A.L.1 encoded by H2al1b in mouse testes (Fig. 4d). In addition, this analysis confirmed the existence of the histone variant H3.3 encoded by the gene Gm10257, for which a specific peptide has been identified, even if its corresponding NCBI protein record has been recently removed (XP_003084990.1).

Other variants may not be detectable by MS in our analysis. For example, a trypsin digestion does not generate any peptides distinguishing mouse H2al1k protein from highly homologous H2A.L.1 variants. Its specific detection would require a more extensive analytical work, e.g. using an alternative protease for protein sample processing, which is beyond the scope of the current work.

Conclusions

MS is a powerful technique to identify histones, their variants and their post-translational modifications but relies on databases with contradictory naming and excessive redundancy. Here we exhaustively collected histone sequences for mouse and human and used manual curation to establish a protein-centric list, MS_HistoneDB, dedicated to the proteomic study of mouse and human histones. Histone variants whose protein status is uncertain in UniProtKB and NCBI but whose protein existence has been established by experimental evidence described in the literature have been included. This work confirmed the expression of isoforms of previously identified TS histone variants and allowed the detection of one H3.3 isoform whose status was so uncertain that its record had been deleted from the NCBI protein database. We hope that this resource will facilitate the study of histone variants, especially by MS, and their functional roles in physiological and pathological contexts.

Methods

Phylogenetic tree representation

Multiple sequence alignments of mouse and human histones were performed using Clustal Omega [85]. Tree data were downloaded in aln format and displayed with iTOLv3 [86].

Analysis of RNA-seq data

Tissue-specific expression data were obtained from Huntley et al. [82] through the Expression Atlas Repository [87]. RNA-seq data at different stages of spermatogenesis were obtained from da Cruz et al. [83]. Data were imported and treated in R using the pheatmap library (https://CRAN.R-project.org/package=pheatmap).

Purification of histones from mouse testis

Histones were extracted from two types of biological samples, namely whole testis and elongated spermatids, to maximize the number of histone variants identified at specific maturation stages of male germ cells. Pure fractions of spermatid nuclei were obtained by sonicating mouse testes, as previously described [38]. Histones were isolated from testis cells and spermatids using sulfuric acid [38] or saline extraction [88]. They were then separated by SDS-PAGE, and proteins were visualized by Coomassie staining.

Sample preparation and analysis by MS

Histones were reduced and alkylated as described previously [89]. Histones were either derivatized with propionic anhydride before and after in-gel trypsin digestion [90], or only submitted to trypsin digestion [89]. The dried extracted peptides were resuspended in 2.5% acetonitrile and 0.05% trifluoroacetic acid and analysed via online nano-LC–MS/MS using an Ultimate 3000 LC system coupled to an LTQ-Orbitrap instrument (CID fragmentation mode) or a Q Exactive Plus instrument (HCD fragmentation mode) (Thermo Fisher Scientific).

Protein sequence database search and manual verification

MS RAW files produced by LC–MS/MS analysis of proteolyzed histones were processed as follows. All MS/MS spectra were submitted to the Mascot program (version 2.5.1) for searching against the MS_HistoneDB protein sequence database. The parse rules for MS_HistoneDB Fasta files in Mascot are using the accession rule >\([^]*\) and the description rule \(.*\). In addition, the taxonomy and sequence report sources are indicated as “Swiss-Prot FASTA” and “FASTA file”, respectively. No taxonomy was specified when using MS_HistoneDB with Mascot Daemon.

Classical histone modifications were included in the variable modifications: N-terminal protein acetylation; Lys acetylation; and Lys and Arg mono- or di-methylation. For all Mascot searches, the tolerance on mass measurement was set to 5 ppm for peptides and to 0.6 or 0.025 Da for fragment ions when considering LTQ-Orbitrap or Q Exactive acquisitions, respectively. Up to four tryptic missed cleavages were allowed for samples that were not propionylated in vitro, as trypsin does not cleave acetylated lysine, a frequent modification. The enzyme ArgC and up to two missed cleavages were specified for the interpretation of data acquired on propionylated samples. All MS/MS spectra leading to the identification of tryptic peptides specific to newly described variants were carefully manually examined: all major intensity fragment peaks had to be interpreted in terms of y/b ions; a continuous sequence of at least five amino acids had to be read in all cases for validation. Proteomics data are available from ProteomeXchange (PXD005489).

Abbreviations

CID: 

collision-induced dissociation

FASTA: 

text-based format for representing protein sequences

HCD: 

higher-energy collisional dissociation

MS: 

mass spectrometry

MS/MS: 

tandem mass spectrometry, used to fragment ions

LC–MS/MS: 

coupling between liquid chromatography and tandem mass spectrometry

NB: 

northern blot

PAGE: 

polyacrylamide gel electrophoresis

TS: 

testis-specific

WB: 

western blot

Declarations

Authors’ contributions

SEK, JG and DP designed the project. SEK collected the data relative to histone entries, which was subsequently curated by SEK, AKS, SK, ARP, DL, DP and JG. Mass spectrometry experiments were performed by SEK and AA, and the MS acquired data analysed by SEK, AA, DP and CB. The first version of the manuscript was written by SEK, DP and JG and then critically revised by AKS, ARP, SK and DL. All authors read and approved the final manuscript.

Acknowledgements

We thank Sophie Rousseaux, Ekaterina Flin and Christophe Battail for their help.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Proteomics data are available from ProteomeXchange under the identifier PXD005489 [131]. RNA-seq data were downloaded from the supplementary information of their original publications [83] or through the Expression Atlas/Array Express repositories [82, 87].

Funding

This work was supported by the Fond d’Intervention of the University Grenoble Alpes (to JG), the Agence Nationale de la Recherche (ANR-11-PDOC-0011 to JG), and the European Union FP7 Marie Curie Action “Career Integration Grant” (304003 to JG). This study also received financial support from the French National Research Agency ANR-10-INBS-08 ProFI, Proteomics French Infrastructure. This research was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
INSERM, U1038, CEA, BIG FR CNRS 3425-BGE, Université Grenoble Alpes
(2)
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health
(3)
CNRS UMR 5309 INSERM U1209, Institute of Advanced Biosciences, Université Grenoble Alpes

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