Dynamic Regulation of Effector Protein Binding to Histone Modifications: The Biology of HP1 Switching

Dormann, Holger L.; Tseng, Boo Shan; Allis, C. David; Funabiki, Hironori; Fischle, Wolfgang

doi:10.4161/cc.5.24.3540

Cited by 61 publications

(71 citation statements)

References 117 publications

(156 reference statements)

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“…We also observed a decrease in global H3K9me1 levels, and others have observed a stress-induced decrease in H3K9ac, which are consistent with our observations of globally increased H3K9 trimethylation (12,28). Crosio et al (9) observed an increase in the H3S10phos mark with a similar regional and temporal specificity to our own observations; whether this change is coupled to the changes in H3K9me3 we see is presently unknown, but of great interest given the role of the H3K9me3-S10phos dual mark as a molecular switch controlling HP1 association with chromatin (29). In contrast, Reul and colleagues have observed increases in phospho acetylation of H3 at serine 10 and lysine 14 following acute stressors; however, these changes were observed in a small Quantification of the stress induced increase in Suv39h2 (*P < 0.03, n = 4) in the dentate gyrus.…”

Section: Discussionsupporting

confidence: 80%

Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response

Hunter

Murakami

Dewell

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

117

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The hippocampus is a highly plastic brain region particularly susceptible to the effects of environmental stress; it also shows dynamic changes in epigenetic marks in response to stress and learning. We have previously shown that, in the rat, acute (30 min) restraint stress induces a substantial, regionally specific, increase in hippocampal levels of the repressive histone H3 lysine 9 trimethylation (H3K9me3). Because of the large magnitude of this effect and the fact that stress can induce the expression of endogenous retroviruses and transposable elements in many systems, we hypothesized that the H3K9me3 response was targeted to these elements as a means of containing potential genomic instability. We used ChIP coupled with next generation sequencing (ChIP-Seq) to determine the genomic localization of the H3K9me3 response. Although there was a general increase in this response across the genome, our results validated this hypothesis by demonstrating that stress increases H3K9me3 enrichment at transposable element loci and, using RT-PCR, we demonstrate that this effect represses expression of intracisternal-A particle endogenous retrovirus elements and B2 short interspersed elements, but it does not appear to have a repressive effect on long interspersed element RNA. In addition, we present data showing that the histone H3K9-specific methyltransferases Suv39h2 is up-regulated by acute stress in the hippocampus, and that this may explain the hippocampal specificity we observe. These results are a unique demonstration of the regulatory effect of environmental stress, via an epigenetic mark, on the vast genomic terra incognita represented by transposable elements.heterochromatin | ncRNA | posttraumatic stress disorder | transposon

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Section: Discussionsupporting

confidence: 80%

Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response

Hunter

Murakami

Dewell

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

117

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“…Namely, HP1 binding to H3K9me3 is antagonized by H3S10 phosphorylation during mitosis (24). We performed a limited screen for genes affected by PRMT6 activity and found that HOXA5 and cyclin D1 expression/repression is responsive to PRMT6 levels, presumably through methylation of H3R2me2.…”

Section: Accelerated Publication: Prmt6 Methylates H3r2mentioning

confidence: 99%

Arginine Methylation of the Histone H3 Tail Impedes Effector Binding

Iberg

Espejo

Cheng

et al. 2008

Journal of Biological Chemistry

180

203

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Histone tail post-translational modification results in changes in cellular processes, either by generating or blocking docking sites for histone code readers or by altering the higher order chromatin structure. H3K4me3 is known to mark the promoter regions of active transcription. Proteins bind H3K4 in a methyl-dependent manner and aid in the recruitment of histone-remodeling enzymes and transcriptional cofactors. The H3K4me3 binders harbor methyl-specific chromatin binding domains, including plant homeodomain, Chromo, and tudor domains. Structural analysis of the plant homeodomains present in effector proteins, as well as the WD40 repeats of WDR5, reveals critical contacts between residues in these domains and H3R2. The intimate contact between H3R2 and these domain types leads to the hypothesis that methylation of this arginine residue antagonizes the binding of effector proteins to the N-terminal tail of H3. Here we show that H3 tail binding effector proteins are indeed sensitive to H3R2 methylation and that PRMT6, not CARM1/PRMT4, is the primary methyltransferase acting on this site. We have tested the expression of a select group of H3K4 effector-regulated genes in PRMT6 knockdown cells and found that their levels are altered. Thus, PRMT6 methylates H3R2 and is a negative regulator of N-terminal H3 tail binding.The tight packing of DNA into chromatin creates a need for mechanisms to relax chromatin and expose DNA for transcription, replication, and DNA repair (1). One of the mechanisms used by the cell to access DNA is the post-translational modification of histone tails. Specifically, methylation of histone tails generates a docking site for effector proteins, which aid in the recruitment of other enzymes necessary for the function at hand. In general, methylation of histone residues lysines 4 and 36 on H3 are correlated with active gene regions, whereas methylation of lysines 9 and 27 on H3 is correlated with repressed gene regions, although exceptions exist (2). The domain types that bind histone tails include the Chromodomain, tudor domains, MBT domains, WD40 repeats, and PHD 5 fingers (3-5).Recently, two groups reported that select PHD fingers have the propensity to bind trimethyl lysine 4 on H3 (6, 7). The structures further showed important aromatic residues in the PHD that cage the methylated lysine but also revealed critical contacts made between the arginine at the second position of the H3 tail and the PHD (8, 9). During this same time, the WD40 domain of WDR5 was reported to complex with the H3 tail (10). The structure of the WD40 repeats of WDR5 revealed arginine 2 of H3, and not lysine 4, buried within the donut hole of the large domain (11,12). Specifically, four amino acids in WDR5 critically interact with arginine 2 (11). In addition, the tudor domains of JMJD2A also bind in an H3K4me3-dependent manner, and again, the H3R2 residue forms critical interactions with an Asp residue of one of the tudor domains (13). The analysis of the structures of these three different domain types bound to t...

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“…Together, these observations suggest that subtle amino acid changes surrounding the aromatic cage can lead to substantial differences in the strength of the cation-interactions between chromodomains and methylated lysine residues. CDY and CDYL2 Respond to a Binary Switch-A binary switch mechanism has been associated with the simultaneous presence of the H3K9me3 and H3S10ph modifications on the same histone tail (H3K9me3S10ph) (19,20). Human HP1 variants are unable to interact with chromatin during mitosis because of the overwhelming presence of serine 10 phosphorylation (17,18).…”

Section: Table 2 Thermodynamic Parameters For Binding To H3 Peptides mentioning

confidence: 99%

“…Sequences immediately preceding the ARK(S/T) motif impact on the specificity of chromodomain interactions. HP1 chromodomains are subject to a binary methyl-phos switch as they are prohibited from interaction with H3K9me3 upon phosphorylation of the adjacent serine 10 in the H3 tail (H3S10ph) (17)(18)(19)(20).Additional complexity in epigenetic control arises from usage of histone variants. For example, substitutions of histone H3 with variants results in indexing of chromatin for transcriptional activation or repression (22,23), and an H3 barcode * This work was supported, in whole or in part, by National Institutes of Health Grants GM064786 (to S. K.), GM63959, and GM53512 (to C. D.…”

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Specificity of the Chromodomain Y Chromosome Family of Chromodomains for Lysine-methylated ARK(S/T) Motifs

Fischle

Franz

Jacobs

et al. 2008

Journal of Biological Chemistry

Self Cite

107

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Previous studies have shown two homologous chromodomain modules in the HP1 and Polycomb proteins exhibit discriminatory binding to related methyllysine residues (embedded in ARKS motifs) of the histone H3 tail. Methylated ARK(S/T) motifs have recently been identified in other chromatin factors (e.g. linker histone H1.4 and lysine methyltransferase G9a). These are thought to function as peripheral docking sites for the HP1 chromodomain. In vertebrates, HP1-like chromodomains are also present in the chromodomain Y chromosome (CDY) family of proteins adjacent to a putative catalytic motif. The human genome encodes three CDY family proteins, CDY, CDYL, and CDYL2. These have putative functions ranging from establishment of histone H4 acetylation during spermiogenesis to regulation of transcription co-repressor complexes. To delineate the biochemical functions of the CDY family chromodomains, we analyzed their specificity of methyllysine recognition. We detected substantial differences among these factors. The CDY chromodomain exhibits discriminatory binding to lysinemethylated ARK(S/T) motifs, whereas the CDYL2 chromodomain binds with comparable strength to multiple ARK(S/T) motifs. Interestingly, subtle amino acid changes in the CDYL chromodomain prohibit such binding interactions in vitro and in vivo. However, point mutations can rescue binding. In support of the in vitro binding properties of the chromodomains, the full-length CDY family proteins exhibit substantial variability in chromatin localization. Our studies underscore the significance of subtle sequence differences in a conserved signaling module for diverse epigenetic regulatory pathways.The human Y chromosome has been thoroughly sequenced and compared with partially sequenced Y chromosomes of chimpanzee and mouse (1-3). The Y chromosomes are believed to be enriched in genes essential for spermatogenesis and testis development. Interstitial Y chromosome deletions are associated with spermatogenic failure and male infertility (1,4,5). One gene that is present in multiple copies on the human Y chromosome is CDY, 5 which exhibits testis-specific expression (1). Interestingly, the mouse Y chromosome does not encode CDY, suggesting a developmentally advanced usage of CDY in primates (3).The human CDY gene seems to be derived from the autosomal homologs CDYL or CDYL2 (Fig. 1, A and B) (6). CDYL is ubiquitously expressed, whereas CDYL2 exhibits selective expression in tissues of testis, prostate, spleen, and leukocytes (6). The mouse genome also encodes related CDYL and CDYL2 genes (Fig. 1B). The presence of CDY-like genes appears to be a hallmark of echinoderm and vertebrate genomes. In sea urchin and chicken genomes we found only one CDY-like gene that corresponds to mammalian CDYL2 (Fig. 1B).CDY family proteins have two conserved domains implicated in histone modification and recognition; that is, a chromodomain followed by an enoyl-coenzyme A hydratase/isomerase (ECH) putative catalytic domain (Fig. 1A). Previously, it was shown that the chromodomain of hum...

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Dynamic Regulation of Effector Protein Binding to Histone Modifications: The Biology of HP1 Switching

Cited by 61 publications

References 117 publications

Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response

Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response

Arginine Methylation of the Histone H3 Tail Impedes Effector Binding

Specificity of the Chromodomain Y Chromosome Family of Chromodomains for Lysine-methylated ARK(S/T) Motifs

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