Alternative titles; symbols
HGNC Approved Gene Symbol: H3C1
Cytogenetic location: 6p22.2 Genomic coordinates (GRCh38) : 6:26,020,451-26,020,958 (from NCBI)
Histones are small, highly basic proteins that consist of a globular domain with unstructured N- and C-terminal tails protruding from the main structure. The histone family contains the core histones H2A (see 613499), H2B (see 609904), H3, and H4 (see 602822) and the linker histone H1 (see 142709). Two full turns of eukaryotic DNA are tightly packaged and ordered in nucleosomes, which consist of an octamer formed by 2 each of the core histones. Nucleosomes are the fundamental unit of chromatin. Histone H1 binds the linker DNA between nucleosomes, thereby increasing the overall stability of chromatin by forming higher order structures. In addition to their role in DNA compartmentalization, histones also play crucial roles in various biologic processes, including gene expression and regulation, DNA repair, chromatin condensation, cell cycle progression, chromosome segregation, and apoptosis. The ability of histones to regulate chromatin dynamics primarily originates from various posttranslational modifications carried out by histone-modifying enzymes. HIST1H3A is a core histone H3 (summary by Marzluff et al. (2002) and Healy et al. (2012)).
For additional background information on histones, histone gene clusters, and the H3 histone family, see GENE FAMILY below.
Like other histones, H3 histones can be subgrouped according to their temporal expression. Replication-dependent histones, such as HIST1H3A through HIST1H3J (602817), HIST2H3C (142780), and HIST3H3 (602820) are mainly expressed during S phase. In contrast, replication-independent histones, or replacement variant histones, such as H3F3A (601128) and H3F3B (601058), can be expressed throughout the cell cycle. Most replication-dependent H3 histone genes, as well as other core histone genes, are located within histone gene cluster-1 (HIST1) on chromosome 6p22-p21. Two other histone gene clusters, HIST2 and HIST3, are located on chromosomes 1q21 and 1q42, respectively, and each contains at least 1 replication-dependent H3 histone gene. In mouse, the Hist1, Hist2, and Hist3 gene clusters are located on chromosomes 13A2-A3, 3F1-F2, and 11B2, respectively. All replication-dependent histone genes are intronless, and they encode mRNAs that lack a poly(A) tail, ending instead in a conserved stem-loop sequence. Unlike replication-dependent histone genes, replication-independent histone genes are solitary genes that are located on chromosomes apart from any other H1 or core histone genes. Some replication-independent histone genes contain introns and encode mRNAs with poly(A) tails. All H3 histone genes in the HIST1 cluster encode the same protein, designated H3.1. The H3 histone gene in the HIST2 cluster, HIST2H3C, encodes a protein designated H3.2, which differs from H3.1 only at residue 96, which is a cysteine in H3.1 and a serine in H3.2. The H3 histone gene in the HIST3 cluster, HIST3H3, encodes a protein that contains ser96 and 4 other changes relative to H3.1 and H3.2. The replication-independent H3 histone genes, H3F3A and H3F3B, encode the same protein, designated H3.3, which is distinct from H3.1 and H3.2 (summary by Marzluff et al. (2002)).
By genomic sequence analysis, Marzluff et al. (2002) identified the mouse and human HIST1H3A genes. They noted that all H3 genes in the HIST1 cluster, including HIST1H3A, encode the same protein, designated H3.1. H3.1 differs from H3.2, which is encoded by HIST2H3C (142780), at only 1 residue, and from histone H3.3, which is encoded by both H3F3A (601128) and H3F3B (601058), at a few residues.
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997) characterized a cluster of 35 histone genes that included H3/a.
By genomic sequence analysis, Marzluff et al. (2002) determined that the HIST1 cluster on chromosome 6p22-p21 contains 55 histone genes, including 10 H3 genes. The HIST1H3A gene is the most telomeric H3 gene within the HIST1 cluster. The HIST1 cluster spans over 2 Mb and includes 2 large gaps (over 250 kb each) where there are no histone genes, but many other genes. The organization of histone genes in the mouse Hist1 cluster on chromosome 13A2-A3 is essentially identical to that in human HIST1. The HIST2 cluster on chromosome 1q21 contains 6 histone genes, including 1 H3 gene (HIST2H3C; 142780), and the HIST3 cluster on chromosome 1q42 contains 3 histone genes, including 1 H3 gene (HIST3H3; 602820). Hist2 and Hist3 are located on mouse chromosomes 3F1-F2 and 11B2, respectively.
H3.1 Histone
Hake et al. (2006) noted that most studies on expression or posttranslational modifications of H3 histones do not differentiate between the H3.1, H3.2, and H3.3 proteins, in part due to their high degree of amino acid identity. By quantitative PCR of 5 human cell lines, they found that the 9 H3.1 genes, 1 H3.2 gene, and 2 H3.3 genes examined were expressed in a cell line-specific manner. All 3 types of H3 genes were highly expressed during S phase in human cell lines, whereas the H3.3 genes were also highly expressed outside of S phase, consistent with their status as replication-independent genes. Using a combination of isotopic labeling and quantitative tandem mass spectrometry, Hake et al. (2006) showed that the H3.1, H3.2, and H3.3 proteins differed in their posttranslational modifications. H3.1 was enriched in marks associated with both gene activation and gene silencing, H3.2 was enriched in repressive marks associated with gene silencing and the formation of facultative heterochromatin, and H3.3 was enriched in marks associated with transcriptional activation. Hake et al. (2006) concluded that H3.1, H3.2, and H3.3 likely have unique functions and should not be treated as equivalent proteins.
Xu et al. (2010) reported that significant amounts of histone H3.3-H4 tetramers split in vivo, whereas most H3.1-H4 tetramers remain intact during mitotic division. Inhibiting DNA replication-dependent deposition greatly reduced the level of splitting events, which suggested that (i) the replication-independent H3.3 deposition pathway proceeds largely by cooperatively incorporating 2 new H3.3-H4 dimers, and (ii) the majority of splitting events occurred during replication-dependent deposition. Xu et al. (2010) concluded that 'silent' histone modifications within large heterochromatic regions are maintained by copying modifications from neighboring preexisting histones without the need for H3-H4 splitting events.
Talbert and Henikoff (2010) reviewed the assembly of canonical nucleosomes, which is thought to begin with a tetramer of 2 H3 molecules and 2 H4 molecules held together by strong bonds between the H3 molecules. H3.1 is the major canonical H3 assembled into chromatin by the histone chaperone CAF1 (see 601246) complex during DNA replication and repair. The replacement histone H3.3 is assembled by the histone regulator A (HIRA; 600237) complex independently of DNA synthesis.
Methylation and Demethylation of H3 Histones
Eukaryotic genomes are organized into discrete structural and functional chromatin domains. Noma et al. (2001) demonstrated that distinct site-specific histone H3 methylation patterns define euchromatic and heterochromatic chromosomal domains within an 47-kb region of the mating type locus in fission yeast. H3 methylated at lysine-9 (H3K9), and its interacting Swi6 protein, are strictly localized to a 20-kb silent heterochromatic interval. In contrast, H3 methylated at lysine-4 (H3K4) is specific to the surrounding euchromatic regions. Two inverted repeats flanking the silent interval serve as boundary elements to mark the borders between heterochromatin and euchromatin. Deletions of these boundary elements leads to spreading of H3K9 methylation and Swi6 into neighboring sequences. Furthermore, the H3K9 methylation and corresponding heterochromatin-associated complexes prevent H3K4 methylation in the silent domain.
Coating of the X chromosome by XIST (314670) RNA is an essential trigger for X inactivation. Heard et al. (2001) reported that methylation of lys9 of histone H3 on the inactive X chromosome occurs immediately after XIST RNA coating and before transcriptional inactivation of X-linked genes. X-chromosomal H3-lys9 methylation occurs during the same window of time as H3-lys9 hypoacetylation and H3-lys4 hypomethylation. Histone H3 modifications thus represent the earliest known chromatin changes during X inactivation. The authors also identified a unique 'hotspot' of H3-lys9 methylation 5-prime to XIST and proposed that this acts as a nucleation center for XIST RNA-dependent spread of inactivation along the X chromosome via H3-lys9 methylation.
Boggs et al. (2002) and Peters et al. (2002) showed that methylation of H3 histone at lys9 occurs in facultative heterochromatin of the inactive X chromosome in female mammals. Posttranslational modifications of histone amino termini are an important regulatory mechanism that induce transitions in chromatin structure, thereby contributing to epigenetic gene control and the assembly of specialized chromosomal subdomains. Methylation of histone H3 at lys9 by site-specific histone methyltransferases marks constitutive heterochromatin. Boggs et al. (2002) found that, in contrast, H3 methylated at lys4 is depleted in the inactive X chromosome, except in 3 'hotspots' of enrichment along its length. They could show that lys9 methylation is associated with promoters of inactive genes, whereas lys4 methylation is associated with active genes on the X chromosome. The data demonstrated that differential methylation at 2 distinct sites of the H3 amino terminus correlates with contrasting gene activities and may be part of a 'histone code' involved in establishing and maintaining facultative heterochromatin.
Peters et al. (2002) showed H3-lys9 methylation is retained through mitosis, indicating that it might provide an epigenetic imprint for the maintenance of the inactive state. Disruption of the 2 site-specific histone methyltransferases in the mouse abolished H3-lys9 methylation of constitutive heterochromatin, but not that of the inactive X chromosome.
In Saccharomyces pombe, Volpe et al. (2002) deleted the argonaute (606228), dicer (606241), and RNA-dependent RNA polymerase gene homologs, which encode part of the machinery responsible for RNA interference. Deletion resulted in the aberrant accumulation of complementary transcripts from centromeric heterochromatic repeats. This was accompanied by transcription of derepression of transgenes integrated at the centromere, loss of histone H3-lys9 methylation, and impairment of centromere function. Volpe et al. (2002) proposed that double-stranded RNA arising from centromeric repeats targets formation and maintenance of heterochromatin through RNA interference.
The higher-order assembly of chromatin imposes structural organization on the genetic information of eukaryotes and is thought to be largely determined by posttranslational modification of histone tails. Hall et al. (2002) studied a 20-kb silent domain at the mating-type region of S. pombe as a model for heterochromatin formation. They found that although histone H3 methylated at lys9 directly recruited heterochromatin protein Swi6/HP1 (604478), the critical determinant for H3-lys9 methylation to spread in cis to be inherited through mitosis and meiosis is Swi6 itself. The authors demonstrated that a centromere homologous repeat present at the silent mating-type region is sufficient for heterochromatin formation at an ectopic site, and that its repressive capacity is mediated by components of the RNA interference machinery. Moreover, the centromere homologous repeat and the RNA interference machinery cooperate to nucleate heterochromatin assembly at the endogenous mating locus but are dispensable for its subsequent inheritance. Hall et al. (2002) concluded that their work defines sequential requirements for the initiation and propagation of regional heterochromatic domains.
Plath et al. (2003) demonstrated that transient recruitment of the EED (605984)-EZH2 (601573) complex to the inactive X chromosome occurs during initiation of X inactivation in both extraembryonic and embryonic cells and is accompanied by H3 lys27 methylation. Recruitment of the complex and methylation on the inactive X depend on Xist (314670) RNA but are independent of its silencing function. Plath et al. (2003) concluded that taken together, their results suggest a role for EED-EZH2-mediated H3 lys27 methylation during initiation of both imprinted and random X inactivation and demonstrate that H3 lys27 methylation is not sufficient for silencing of the inactive X.
Methylation of histone tails has been implicated in long-term epigenetic memory. Methylated H3K4 is a generally conserved mark for euchromatic, transcriptionally active regions. Rougeulle et al. (2003) described a profile of H3K4 dimethylation that was specific for monoallelically expressed genes. Both X-linked genes subject to X inactivation and autosomal imprinted genes had dimethylated H3K4 restricted to their promoter regions. In contrast, high levels of H3K4 dimethylation were found in both promoters and exonic parts of autosomal genes and of X-linked genes that escaped X inactivation. Rougeulle et al. (2003) suggested that this pattern of promoter-restricted H3K4 dimethylation, already present in totipotent cells, may be causally related to the long-term programming of allelic expression and may provide an epigenetic mark for monoallelically expressed genes.
Huyen et al. (2004) found that the tandem tudor domain of 53BP1 (605230) bound histone H3 methylated on lys79 in vitro. Suppression of DOT1L (607375), the enzyme that methylates lys79 of histone H3, also inhibited recruitment of 53BP1 to double-strand breaks. Because methylation of histone H3 lys79 was unaltered in response to DNA damage, Huyen et al. (2004) proposed that 53BP1 senses double-strand breaks indirectly through changes in higher-order chromatin structure that expose the 53BP1 binding site.
Cha et al. (2005) showed that AKT (164730) phosphorylates EZH2 (601573) at serine-21 and suppresses its methyltransferase activity by impeding EZH2 binding to histone H3, which results in a decrease of lysine-27 trimethylation and derepression of silenced genes. Cha et al. (2005) concluded that their results imply that AKT regulates the methylation activity, through phosphorylation of EZH2, which may contribute to oncogenesis.
Lee et al. (2005) showed that BHC110 (609132)-containing complexes showed a near 5-fold increase in demethylation of H3K4 compared to recombinant BHC110. Furthermore, recombinant BHC110 was unable to demethylate H3K4 on nucleosomes, but BHC110-containing complexes readily demethylated nucleosomes. In vitro reconstitution of the BHC complex using recombinant subunits revealed an essential role for the REST corepressor CoREST (607675), not only in stimulating demethylation on core histones but also promoting demethylation of nucleosomal substrates. Lee et al. (2005) found that nucleosomal demethylation was the result of CoREST enhancing the association between BHC110 and nucleosomes. Depletion of CoREST in in vivo cell culture resulted in derepression of REST-responsive gene expression and increased methylation of H3K4. Taken together, Lee et al. (2005) concluded that their results highlight an essential role for CoREST in demethylation of H3K4 both in vitro and in vivo.
Wysocka et al. (2006) showed that a plant homeodomain (PHD) finger of nucleosome remodeling factor (NURF), an ISWI-containing ATP-dependent chromatin-remodeling complex, mediates a direct preferential association with trimethylated H3K4 tails. Depletion of trimethylated H3K4 causes partial release of the NURF subunit BPTF (601819) from chromatin and defective recruitment of the associated ATPase, SNF2L1 (SMARCA1; 300012), to the HOXC8 (142970) promoter. Loss of BPTF in Xenopus embryos mimics WDR5 (609012) loss-of-function phenotypes, and compromises spatial control of Hox gene expression. Wysocka et al. (2006) suggested that WDR5 and NURF function in a common biologic pathway in vivo, and that NURF-mediated ATP-dependent chromatin remodeling is directly coupled to H3K4 trimethylation to maintain HOX gene expression patterns during development.
Shi et al. (2006) identified a novel class of methylated H3K4 effector domains, the PHD domains of the ING (see 601566) family of tumor suppressor proteins. The ING PHD domains are specific and highly robust binding modules for tri- and dimethylated H3K4. ING2 (604215), a native subunit of a repressive mSin3a (607776)-HDAC1 (601241) histone deacetylase complex, binds with high affinity to the trimethylated species. In response to DNA damage, recognition of trimethylated H3K4 by the ING2 PHD domain stabilizes the mSin3a-HDAC1 complex in promoters of proliferation genes. In addition, ING2 modulates cellular responses to genotoxic insults, and these functions are critically dependent on ING2 interaction with trimethylated H3K4. Shi et al. (2006) concluded that trimethylation of K4 on histone 3 plays a pivotal role in gene repression and potentially in tumor suppressor mechanisms.
In a search for proteins and complexes interacting with trimethylated histone H3K9, Cloos et al. (2006) identified JMJD2C (605469). Cloos et al. (2006) showed that 3 members of the JMJD2 subfamily of proteins demethylate tri- or dimethylated H3K9 in vitro through a hydroxylation reaction requiring iron and alpha-ketoglutarate as cofactors. They demonstrated also that ectopic expression of JMJD2C or other JMJD2 members markedly decreased tri- and dimethylated H3K9 levels, increased monomethylated H3K9, delocalized HP1 (see 604478), and reduced heterochromatin in vivo. In agreement with studies indicating a contribution of JMJD2C to tumor development, inhibition of JMJD2C expression decreased cell proliferation.
Klose et al. (2006) demonstrated that JMJD2A is capable of removing the trimethyl group from modified H3K9 and H3K36. Overexpression of JMJD2A abrogated recruitment of HP1 to heterochromatin, indicating a role for JMJD2A in antagonizing methylated H3K9 nucleated events. siRNA-mediated knockdown of JMJD2A led to increased levels of H3K9 methylation and upregulation of a JMJD2A target gene, ASCL2 (601886), indicating that JMJD2A may function in euchromatin to remove histone methylation marks that are associated with active transcription.
Mikkelsen et al. (2007) reported the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells. By obtaining over 4 billion bases of sequence from chromatin immunoprecipitated DNA, they generated genomewide chromatin-state maps of mouse embryonic stem cells, neural progenitor cells, and embryonic fibroblasts. Mikkelsen et al. (2007) found that H3 lysine-4 and H3 lysine-27 trimethylation effectively discriminated genes that are expressed, poised for expression, or stably repressed, and therefore reflected cell state and lineage potential. H3 lysine-36 trimethylation marks primary coding and noncoding transcripts, facilitating gene annotation. Trimethylation of lysine-9 and lysine-20 is detected at satellite, telomeric, and active long-terminal repeats, and can spread into proximal unique sequences. H3 lysine-4 and lysine-9 trimethylation marks imprinting control regions. Chromatin state could be read in an allele-specific manner by using single-nucleotide polymorphisms. Mikkelsen et al. (2007) concluded that their study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations.
Using mass spectrometry, Ooi et al. (2007) identified the main proteins that interacted in vivo with the product of an epitope-tagged allele of the endogenous DNMT3L (606588) gene as DNMT3A2 (602769), DNMT3B (602900), and the 4 core histones. Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine-4 of histone H3 but was insensitive to modifications at other positions. Crystallographic studies of human DNMT3L showed that the protein has a carboxy-terminal methyltransferase-like domain and an N-terminal cysteine-rich domain. Cocrystallization of DNMT3L with the tail of histone H3 revealed that the tail bound to the cysteine-rich domain of DNMT3L, and substitution of key residues in the binding site eliminated the H3 tail-DNMT3L interaction. Ooi et al. (2007) concluded that DNMT3L recognizes histone H3 tails that are unmethylated at lysine-4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2.
Lan et al. (2007) reported that, in contrast to the PHD fingers of the bromodomain PHD finger transcription factor (BPTF; 601819) and inhibitor of growth family 2 (ING2; 604215), which bind methylated H3K4, the PHD finger of BHC80 binds unmethylated H3K4 (H3K4me0), and this interaction is specifically abrogated by methylation of H3K4. The crystal structure of the PHD finger of BHC80 bound to an unmodified H3 peptide revealed the structural basis of the recognition of H3K4me0. Knockdown of BHC80 by RNA inhibition resulted in the derepression of LSD1 target genes, and this repression was restored by the reintroduction of wildtype BHC80 but not by a PHD finger mutant that could not bind H3. Chromatin immunoprecipitation showed that BHC80 and LSD1 depend reciprocally on one another to associate with chromatin. Lan et al. (2007) concluded that their findings coupled the function of BHC80 to that of LSD1, and indicated that unmodified H3K4 is part of the histone code. The authors further raised the possibility that the generation and recognition of the unmodified state on histone tails in general might be just as crucial as posttranslational modifications of histone for chromatin and transcriptional regulation.
Lee et al. (2007) showed that human UTX (300128), a member of the Jumonji C family of proteins, is a di- and trimethyl H3K27 demethylase. UTX occupies the promoters of HOX gene clusters (see 142950) and regulates their transcriptional output by modulating the recruitment of polycomb repressive complex 1 (PRC1) and the monoubiquitination of histone H2A (see 602786). Moreover, UTX associates with mixed-lineage leukemia (MLL) 2/3 complexes (602113, 606833, respectively), and during retinoic acid signaling events, the recruitment of the UTX complex to HOX genes results in H3K27 demethylation and a concomitant methylation of H3K4. Lee et al. (2007) concluded that their results suggested a concerted mechanism for transcriptional activation in which cycles of H3K4 methylation by MLL2/3 are linked with the demethylation of H3K27 through UTX.
The arginine at position 2 of histone H3 (H3R2) is asymmetrically dimethylated (H3R2me2a) in mammalian cells (Torres-Padilla et al., 2007). Kirmizis et al. (2007) demonstrated that H3R2 is also methylated in S. cerevisiae, and by using an antibody specific for H3R2me2a in a chromatin immunoprecipitation (ChIP)-on-chip analysis, they determined the distribution of this modification on the entire yeast genome. They found that H3R2me2A is enriched throughout all heterochromatic loci and inactive euchromatic genes and is present at the 3-prime end of moderately transcribed genes. In all cases the pattern of H3R2 methylation is mutually exclusive with the trimethyl form of H3K4 (H3K4me3). Kirmizis et al. (2007) showed that methylation at H3R2 abrogates the trimethylation of H3K4 by the Set1 methyltransferase (see 611052). The specific effect on H3K4me3 results from the occlusion of Spp1, a Set1 methyltransferase subunit necessary for trimethylation. Kirmizis et al. (2007) concluded that the inability of Spp1 to recognize H3 methylated at R2 prevents Set1 from trimethylating H3K4. Kirmizis et al. (2007) stated that their results provided the first mechanistic insight into the function of arginine methylation on chromatin.
Following up on the observation that asymmetric dimethylation of histone H3R2 (H3R2me2a) countercorrelates with di- and trimethylation of H3K4 (H3K4me2, H3K4me3) on human promoters, Guccione et al. (2007) demonstrated that the arginine methyltransferase PRMT6 (608274) catalyzes H3R2 dimethylation in vitro and controls global levels of H3R2me2a in vivo. H3R2 methylation by PRMT6 was prevented by the presence of H3K4me3 on the H3 tail. Conversely, the H3R2me2a mark prevented methylation of H3K4 as well as binding to the H3 tail by an ASH2 (604782)/WDR5 (609012)/MLL (159555) family methyltransferase complex. Chromatin immunoprecipitation showed that H3R2me2a was distributed within the body and at the 3-prime end of human genes, regardless of their transcriptional state, whereas it was selectively and locally depleted from active promoters, coincident with the presence of H3K4me3. Guccione et al. (2007) concluded that hence, the mutual antagonism between H3R2 and H3K4 methylation, together with the association of MLL family complexes with the basal transcription machinery, may contribute to the localized patterns of H3K4 trimethylation characteristic of transcriptionally poised or active promoters in mammalian genomes.
Perillo et al. (2008) analyzed how H3 histone methylation and demethylation control expression of estrogen-responsive genes and showed that a DNA-bound estrogen receptor (see ESRA, 133430) directs transcription by participating in bending chromatin to contact the RNA polymerase II (see 180660) recruited to the promoter. This process is driven by receptor-targeted demethylation of H3K9 at both enhancer and promoter sites and is achieved by activation of resident LSD1 (609132) demethylase. Localized demethylation produces hydrogen peroxide, which modifies the surrounding DNA and recruits 8-oxoguanine-DNA glycosylase 1 (601982) and topoisomerase II-beta (126431), triggering chromatin and DNA conformational changes that are essential for estrogen-induced transcription. Perillo et al. (2008) concluded that their data showed a strategy that uses controlled DNA damage and repair to guide productive transcription.
Using high-resolution SNP genotyping to identify regions of genomic gain and loss in 212 medulloblastoma tumors (155255), Northcott et al. (2009) identified several focal genetic events in genes targeting histone methylation at lysine residues, particularly that of H3K9. In vitro studies showed that restoring expression of genes controlling H3K9 methylation greatly diminished proliferation of medulloblastoma cells. Northcott et al. (2009) postulated that defective control of the histone code may contribute to the pathogenesis of medulloblastoma.
Ciccone et al. (2009) demonstrated that KDM1B (613081) functions as a H3K4 demethylase and is required for de novo DNA methylation of some imprinted genes in oocytes. KDM1B is highly expressed in growing oocytes where genomic imprints are established. Targeted disruption of the gene encoding KDM1B had no effect on mouse development or oogenesis. However, oocytes from KDM1B-deficient females showed a substantial increase in H3K4 methylation and failed to set up the DNA methylation marks at 4 out of 7 imprinted genes examined. Embryos derived from these oocytes showed biallelic expression or biallelic suppression of the affected genes and died before midgestation. Ciccone et al. (2009) concluded that demethylation of H3K4 is critical for establishing the DNA methylation imprints during oogenesis.
Nucleosomes are largely replaced by protamine in mature human sperm. Hammoud et al. (2009) showed that the retained nucleosomes were significantly enriched at loci of developmental importance, including imprinted gene clusters, microRNA clusters, HOX gene clusters, and promoters of stand-alone developmental transcription and signaling factors. Histone modifications localized to particular developmental loci. H3K4me2 was enriched at certain developmental promoters, whereas large blocks of H3K4me3 localized to a subset of developmental promoters, regions in HOX clusters, certain noncoding RNAs, and generally to paternally expressed imprinted loci, but not paternally repressed loci. H3K27me3 was significantly enriched at developmental promoters that were repressed in early embryos, including many bivalent promoters (i.e., bearing both H3K4me3 and H3K27me3) in embryonic stem cells. Developmental promoters were generally DNA hypomethylated in sperm, but they acquired methylation during differentiation. Hammoud et al. (2009) concluded that epigenetic marking in sperm is extensive and is correlated with developmental regulators.
Maze et al. (2010) identified an essential role for H3K9 dimethylation and the lysine dimethyltransferase G9a (604599) in cocaine-induced structural and behavioral plasticity in mouse. Repeated cocaine administration reduced global levels of H3K9 dimethylation in the nucleus accumbens. This reduction in histone methylation was mediated through the repression of G9a in this brain region, which was regulated by the cocaine-induced transcription factor delta-FosB (164772). Using conditional mutagenesis and viral-mediated gene transfer, Maze et al. (2010) found that G9a downregulation increased the dendritic spine plasticity of nucleus accumbens neurons and enhanced the preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine.
Luco et al. (2010) demonstrated a direct role for histone modifications, specifically, trimethylation of H3 at lys36 (H3-K36me3), in alternative splicing. The authors found that MRG15 (607303) distribution along the polypyrimidine tract-binding protein (PTB; 600693)-dependent alternatively spliced genes FGFR2 (176943), TPM2 (190990), TPM1 (191010), and PKM2 (179050), but not along the control gene CD44 (107269), mimicked H3-K36me3 distribution. Overexpression of MRG15 was sufficient to force exclusion of the PTB-dependent exons but did not significantly alter the inclusion levels of CD44 exon v6. Additional experiments led Luco et al. (2010) to conclude that the chromatin-binding protein MRG15 is a modulator of PTB-dependent alternative splice site selection. The results of Luco et al. (2010) led them to propose the existence of an adaptor system for the reading of histone marks by the pre-mRNA splicing machinery. The adaptor system consists of histone modifications, a chromatin-binding protein that reads the histone marks, and an interacting splicing regulator. Luco et al. (2010) concluded that for a subset of PTB-dependent genes, the adaptor system consists of H3-K36me3, its binding protein MRG15, and the splicing regulator PTBP1.
He et al. (2010) performed genomewide mapping of nucleosomes marked with H3K4me2 in upstream AR-binding enhancers in LNCaP prostate cancer cells before and following stimulation by dihydrotestosterone (DHT). They found 3 nucleosomes containing H3K4me2 associated with AR-binding sites in the absence of DHT, including 2 stable flanking nucleosomes positioned about 200 bp apart, and a labile central nucleosome that occluded the actual AR-binding site. Following stimulation, H3K4me2 was detected only in the 2 flanking sites. The central occluding nucleosome had a higher A/T content than the flanking nucleosomes, and its histone octamer was more likely to contain the H2A.Z variant. He et al. (2010) concluded that apparent differences in nucleosome stability may result from the combination of DNA sequence, histone octamer composition, and transcription factor binding.
The histone methylase SUV39H1 (300254) participates in the trimethylation of histone H3 on lysine-9 (H3K9me3), a modification that provides binding sites for heterochromatin protein 1-alpha (HP1-alpha; 604478) and promotes transcriptional silencing. This pathway was initially associated with heterochromatin formation and maintenance but can also contribute to the regulation of euchromatic genes. Allan et al. (2012) proposed that the SUV39H1-H3K9me3-HP1-alpha pathway participates in maintaining the silencing of TH1 loci, ensuring TH2 lineage stability. In TH2 cells that are deficient in SUV39H1, the ratio between trimethylated and acetylated H3K9 is impaired, and the binding of HP1-alpha at the promoters of silenced TH1 genes is reduced. Despite showing normal differentiation, both SUV39H1-deficient TH2 cells and HP1-alpha-deficient TH2 cells, in contrast to wildtype cells, expressed TH1 genes when recultured under conditions that drive differentiation into TH1 cells. In a mouse model of TH2-driven allergic asthma, the chemical inhibition or loss of SUV39H1 skewed T-cell responses towards TH1 responses and decreased the lung pathology.
Yuan et al. (2012) reported that polycomb repressive complex-2 (PRC2) activity is regulated by the density of its substrate nucleosome arrays. Neighboring nucleosomes activate the PRC2 complex with a fragment of their H3 histones (ala31 to arg42). Yuan et al. (2012) also identified mutations on PRC2 subunit Suz12 (606245) that impair its binding and response to the activating peptide and its ability in establishing H3K27 trimethylation levels in vivo. In mouse embryonic stem cells, local chromatin compaction occurs before the formation of trimethylated H3K27 upon transcription cessation of the retinoic acid-regulated gene CYP26A1 (602239). Yuan et al. (2012) proposed that PRC2 can sense the chromatin environment to exert its role in the maintenance of transcriptional states.
Phosphorylation and Dephosphorylation of H3 Histones
During the immediate-early response of mammalian cells to mitogens, histone H3 is rapidly and transiently phosphorylated by 1 or more kinases. Sassone-Corsi et al. (1999) demonstrated that RSK2 (300075), a member of the pp90(RSK) family of kinases implicated in growth control, was required for epidermal growth factor (EGF; 131530)-stimulated phosphorylation of H3. H3 appears to be a direct or indirect target of RSK2, suggesting to Sassone-Corsi et al. (1999) that chromatin remodeling might contribute to mitogen-activated protein kinase-regulated gene expression.
Anest et al. (2003) demonstrated nuclear accumulation of IKK-alpha (IKKA; 600664) after cytokine exposure, suggesting a nuclear function for this protein. Consistent with this, chromatin immunoprecipitation assays revealed that IKKA was recruited to the promoter regions of NF-kappa-B (164011)-regulated genes on stimulation with tumor necrosis factor-alpha (191160). Notably, NF-kappa-B-regulated gene expression was suppressed by the loss of IKKA, and this correlated with a complete loss of gene-specific phosphorylation of histone H3 on serine-10, a modification previously associated with positive gene expression. Furthermore, Anest et al. (2003) showed that IKKA can directly phosphorylate histone H3 in vitro, suggesting a new substrate for this kinase. Anest et al. (2003) proposed that IKKA is an essential regulator of NFKB-dependent gene expression through control of promoter-associated histone phosphorylation after cytokine exposure.
Yamamoto et al. (2003) independently demonstrated that IKKA functions in the nucleus to activate the expression of NF-kappa-B-responsive genes after stimulation with cytokines. IKKA interactions with CREB-binding protein (600140) and in conjunction with RELA (164014) is recruited to NF-kappa-B-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone H3. Yamamoto et al. (2003) concluded that their results define a new nuclear role of IKKA in modifying histone function that is critical for the activation of NF-kappa-B-directed gene expression.
Fischle et al. (2005) demonstrated that HP1-alpha (604478), HP1-beta (604511), and HP1-gamma (604477) are released from chromatin during the M phase of the cell cycle, even though trimethylation levels of H3K9 remain unchanged. However, the additional transient modification of histone H3 by phosphorylation of ser10 next to the more stable methyl-lys9 mark is sufficient to eject HP1 proteins from their binding sites. Inhibition or depletion of the mitotic kinase Aurora B (604970), which phosphorylates histone H3 on ser10, causes retention of HP1 proteins on mitotic chromosomes, suggesting that H3 ser10 phosphorylation is necessary for the dissociation of HP1 from chromatin in M phase. Fischle et al. (2005) concluded that their findings establish a regulatory mechanism of protein-protein interactions, through a combinatorial readout of 2 adjacent posttranslational modifications: a stable methylation and a dynamic phosphorylation mark.
Dawson et al. (2009) showed that human JAK2 (147796) is present in the nucleus of hematopoietic cells and directly phosphorylates tyr41 (Y41) on histone H3. Heterochromatin protein 1-alpha (HP1-alpha, 604478), but not HP1-beta (604511), specifically binds to this region of H3 through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2 prevents this binding. Inhibition of JAK2 activity in human leukemic cells decreases both the expression of hematopoietic oncogene LMO2 (180385) and the phosphorylation of H3Y41 at its promoter, while simultaneously increasing the binding of HP1-alpha at the same site. Dawson et al. (2009) concluded that their results identified a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and revealed a direct mechanistic link between 2 genes, JAK2 and LMO2, involved in normal hematopoiesis and leukemia.
Metzger et al. (2010) demonstrated that phosphorylation of histone H3 at threonine-6 (H3T6) by protein kinase C (PKC)-beta-1 (176970) is the key event that prevents LSD1 (609132) from demethylating H3K4 during androgen receptor (AR; 313700)-dependent gene activation. In vitro, histone H3 peptides methylated at lysine-4 and phosphorylated at threonine-6 were no longer LSD1 substrates. In vivo, PKC-beta-1 colocalized with AR and LSD1 on target gene promoters and phosphorylated H3T6 after androgen-induced gene expression. RNAi-mediated knockdown of PKC-beta-1 abrogated H3T6 phosphorylation, enhanced demethylation at H3K4, and inhibited AR-dependent transcription. Activation of PKCB1 requires androgen-dependent recruitment of the gatekeeper kinase protein kinase C-related kinase 1 (PRK1; 601032). Notably, increased levels of PKCB1 and phosphorylated H3T6 (H3T6ph) positively correlated with high Gleason scores of prostate carcinomas, and inhibition of PKC-beta-1 blocked AR-induced tumor cell proliferation in vitro and cancer progression of tumor xenografts in vivo. Together, Metzger et al. (2010) concluded that androgen-dependent kinase signaling leads to the writing of the new chromatin mark H3T6ph, which in consequence prevents removal of active methyl marks from H3K4 during AR-stimulated gene expression.
Wang et al. (2010) showed that phosphorylation of histone H3 threonine-3 (H3T3) by haspin (609240) is necessary for chromosomal passenger complex (CPC) accumulation at centromeres and that the CPC subunit survivin (603352) binds directly to phosphorylated H3T3 (H3T3ph). A nonbinding survivin-D70A/D71A mutant did not support centromeric CPC concentration, and both haspin depletion and survivin-D70A/D71A mutation diminished centromere localization of the kinesin MCAK (604538) and the mitotic checkpoint response to taxol. Survivin-D70A/D71A mutation and microinjection of H3T3ph-specific antibody both compromised centromeric Aurora B (604970) functions but did not prevent cytokinesis. Therefore, Wang et al. (2010) concluded that H3T3ph generated by haspin positions the chromosomal passenger complex at centromeres to regulate selected targets of Aurora B during mitosis.
Kelly et al. (2010) demonstrated that H3T3ph is directly recognized by an evolutionarily conserved binding pocket in the BIR domain of the CPC subunit survivin. This binding mediates recruitment of the CPC to chromosomes and the resulting activation of its kinase subunit Aurora B. Consistently, modulation of the kinase activity of haspin, which phosphorylates H3T3, leads to defects in the Aurora B-dependent processes of spindle assembly and inhibition of nuclear reformation. Kelly et al. (2010) concluded that their findings established a direct cellular role for mitotic H3T3 phosphorylation, which is read and translated by the CPC to ensure accurate cell division.
Yamagishi et al. (2010) showed that phosphorylation of H3T3 mediated by haspin cooperates with bub1 (602452)-mediated histone 2A-serine-121 (H2A-S121) phosphorylation in targeting the CPC to the inner centromere in fission yeast and human cells. Phosphorylated H3T3 promotes nucleosome binding of survivin, whereas phosphorylated H2A-S121 facilitates the binding of shugoshin (609168), the centromeric CPC adaptor. Haspin colocalizes with cohesin by associating with Pds5 (see 613200), whereas bub1 localizes at kinetochores. Thus, Yamagishi et al. (2010) concluded that the inner centromere is defined by intersection of 2 histone kinases.
Healy et al. (2012) reviewed the role of phosphorylation of H3 at ser10 and ser28 by MSK1 (RPS6KA5; 603607)/MSK2 (RPS6KA4; 603606) in the regulation of immediate-early genes, such as JUN (165160) and FOS (164810).
Acetylation and Deacetylation of H3 Histones
Agalioti et al. (2002) found that only a small subset of lysines in histones H3 and H4 are acetylated in vivo by the GCN5 acetyltransferase (see 602301) during activation of the interferon-beta gene (IFNB; 147640). Reconstitution of recombinant nucleosomes bearing mutations in these lysine residues revealed the cascade of gene activation via a point-by-point interpretation of the histone code through the ordered recruitment of bromodomain-containing transcription complexes. Acetylation of histone H4 lys8 mediates recruitment of the SWI/SNF complex (see 603111), whereas acetylation of lys9 and lys14 in histone H3 is critical for the recruitment of TFIID (see 313650). Thus, the information contained in the DNA address of the enhancer is transferred to the histone N termini by generating novel adhesive surfaces required for the recruitment of transcription complexes.
Masumoto et al. (2005) showed that acetylation of the lysine at position 56 (K56) in histone H3 is an abundant modification of newly synthesized histone H3 molecules that are incorporated into chromosomes during S phase. Defects in the acetylation of K56 in histone H3 result in sensitivity to genotoxic agents that cause DNA strand breaks during replication. In the absence of DNA damage, the acetylation of K56 largely disappears in G2. In contrast, cells with DNA breaks maintain high levels of acetylation, and the persistence of the modification is dependent on DNA damage checkpoint proteins. Masumoto et al. (2005) suggested that the acetylation of histone H3 K56 in S. cerevisiae creates a favorable chromatin environment for DNA repair and that a key component of the DNA damage response is to preserve this acetylation.
Michishita et al. (2008) showed that the human SIRT6 protein (606211) is an NAD(+)-dependent histone H3K9 deacetylase that modulates telomeric chromatin. They showed that SIRT6 associates specifically with telomeres, and SIRT6 depletion led to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence. Moreover, SIRT6-depleted cells exhibited abnormal telomere structures that resemble defects observed in Werner syndrome (277700), a premature aging disorder. At telomeric chromatin, SIRT6 deacetylated H3K9 and was required for the stable association of RECQL2 (604611), the factor that is mutated in Werner syndrome. Michishita et al. (2008) proposed that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metabolism and function. The authors concluded that their findings constituted the first identification of a physiologic enzymatic activity of SIRT6, and linked chromatin regulation by SIRT6 to telomere maintenance and to a human premature aging syndrome.
Das et al. (2009) demonstrated that the histone acetyltransferase CBP (600140) in flies, and CBP and p300 (602700) in humans, acetylate H3K56, whereas Drosophila sir2 and human SIRT1 (604479) and SIRT2 (604480) deacetylate H3K56 acetylation. The histone chaperones ASF1A (609189) in humans and Asf1 in Drosophila are required for acetylation of H3K56 in vivo, whereas the histone chaperone CAF1 (see 601245) in humans and Caf1 in Drosophila are required for the incorporation of histones bearing this mark into chromatin. Das et al. (2009) showed that, in response to DNA damage, histones bearing acetylated K56 are assembled into chromatin in Drosophila and human cells, forming foci that colocalize with sites of DNA repair. Furthermore, acetylation of H3K56 is increased in multiple types of cancer, correlating with increased levels of ASF1A in these tumors. Das et al. (2009) concluded that their identification of multiple proteins regulating the levels of H3K56 acetylation in metazoans will allow future studies of this critical and unique histone modification that couples chromatin assembly to DNA synthesis, cell proliferation, and cancer.
Zaidi et al. (2013) compared the incidence of de novo mutations in 362 severe congenital heart disease cases and 264 controls by analyzing exome sequencing of parent-offspring trios. Congenital heart disease cases showed a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios were seen across the main classes of severe congenital heart disease. Zaidi et al. (2013) found a marked excess of de novo mutations in genes involved in the production, removal, or reading of histone 3 lysine-4 (H3K4) methylation or ubiquitination of H2BK120 (see 609904), which is required for H3K4 methylation. There were also 2 de novo mutations in SMAD2 (601366), which regulates H3K27 methylation in the embryonic left right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes.
Lu et al. (2016) reported that histone H3 lysine-to-methionine mutations at codon 36 (H3K36M) impair the differentiation of mesenchymal progenitor cells and generate undifferentiated sarcoma in mice. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases including NSD1 (606681), NSD2 (602952), and SETD2 (612778). Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. After the loss of H3K36 methylation, a genomewide gain in H3K27 methylation leads to a redistribution of polycomb repressive complex-1 (PRC1) and derepression of its target genes known to block mesenchymal differentiation. Lu et al. (2016) commented that their findings are mirrored in human undifferentiated sarcomas in which novel K36M/I mutations in H3.1 are identified.
As revealed by the structure of the chromodomain of HP1 (see 604511) bound to a histone H3 peptide dimethylated at N-zeta of lys9, Nielsen et al. (2002) showed that HP1 uses an induced-fit mechanism to recognize the methylation of lys9. The side chain of lys9 is almost fully extended and surrounded by residues that are conserved in many other chromodomains. The QTAR peptide sequence preceding lys9 performs most of the additional interactions with the chromodomain, with HP1 residues val23, leu40, trp42, leu58, and cys60 appearing to be a major determinant of specificity by binding the key buried ala7. Nielsen et al. (2002) concluded that their findings predict which other chromodomains will bind methylated proteins and suggest a motif that they might recognize.
Using deuterium exchange/mass spectrometry coupled with hydrodynamic measures, Black et al. (2004) demonstrated that CENPA (117139) and histone H4 form subnucleosomal tetramers that are more compact and conformationally more rigid than the corresponding tetramers of histones H3 and H4. Substitution into histone H3 of the domain of CENPA responsible for compaction was sufficient to direct it to centromeres. Thus, Black et al. (2004) concluded that the centromere-targeting domain of CENPA confers a unique structural rigidity to the nucleosomes into which it assembles, and is likely to have a role in maintaining centromere identity.
Marzluff et al. (2002) provided a nomenclature for replication-dependent histone genes located within the HIST1, HIST2, and HIST3 clusters. The symbols for these genes all begin with HIST1, HIST2, or HIST3 according to which cluster they are located in. The H2A, H2B, H3, and H4 genes were named systematically according to their location within the HIST1, HIST2, and HIST3 clusters. For example, HIST1H3A is the most telomeric H3 gene within HIST1, and HIST1H3J (602817) is the most centromeric. In contrast, the H1 genes, all of which are located within HIST1, were named according to their mouse homologs. Thus, HIST1H1A (142709) is homologous to mouse H1a, HIST1H1B (142711) is homologous to mouse H1b, and so on.
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