Transcription regulation by histone modifications is a major contributing factor to the structural and functional diversity in biology. These modifications are encrypted as histone codes or histone languages and function to establish and maintain heritable epigenetic codes that define the identity and the fate of the cell. Despite recent advances revealing numerous histone modifications associated with transcription regulation, how such modifications dictate the process of transcription is not fully understood. Here we describe spatial and temporal analyses of the histone modifications that are introduced during estrogen receptor α (ERα)-activated transcription. We demonstrated that aborting RNA polymerase II caused a disruption of the histone modifications that are associated with transcription elongation but had a minimal effect on modifications deposited during transcription initiation. We also found that the histone H3S10 phosphorylation mark is catalyzed by mitogen- and stress-activated protein kinase 1 (MSK1) and is recognized by a 14-3-3ζ/14-3-3ε heterodimer through its interaction with H3K4 trimethyltransferase SMYD3 and the p52 subunit of TFIIH. We showed that H3S10 phosphorylation is a prerequisite for H3K4 trimethylation. In addition, we demonstrated that SET8/PR-Set7/KMT5A is required for ERα-regulated transcription and its catalyzed H4K20 monomethylation is implicated in both transcription initiation and elongation. Our experiments provide a relatively comprehensive analysis of histone modifications associated with ERα-regulated transcription and define the biological meaning of several key components of the histone code that governs ERα-regulated transcription.
"Regulation of TFF1 expression has been extensively analysed, and the reported evidence of DNA methylation (Métivier et al., 2008) and histone modifications (Li et al., 2011) shed further light on the role of the epigenetic control. Moreover a number of transcription factors were described to bind its promoter and control its expression: the already mentioned Estrogen Receptor along with Sp proteins (Sun et al., 2005), as well as TNF-␣ activated NF-B (Koike et al., 2007) and the AP-1 complex (Baron et al., 2007). "
"Epigenetic regulation of the AHR pathway, including the Ahr gene itself, is likely to play an important role in the control of the expression of its target genes, and thus, in its biological functions and its mechanistic role in xenobiotic metabolism and developmental toxicity. Of the three protein kinases detected, MSK1/2 has been shown to induce the expression of early stress response genes, such as c-fos and c-jun, by phosphorylation of H3S10 after mitogen stimulation (Soloaga et al., 2003), and to regulate TFF1 transcription by phosphorylating H3S10 in the TFF1 promoter in an ER␣-dependent manner (Li et al., 2011b). In addition, MSK1/2 has been associated with the activation of the AHR pathway for quite some time. "
[Show abstract][Hide abstract] ABSTRACT: Aryl hydrocarbon receptor (AHR) activation by xenobiotic ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is key to their toxicity. Following activation and nuclear translocation, AHR heterodimerizes with the AHR nuclear translocator (ARNT) and binds to AHR response elements (AhREs) in the enhancer of target genes, of which Cyp1a1 is the prototype. Previously, we showed that concomitant with AHR binding, histone H3 in the Cyp1a1 enhancer-promoter AhRE cluster became phosphorylated in serine-10 (H3S10), suggesting that the ligand-activated AHR recruited one or more kinases to the enhancer chromatin to phosphorylate this residue. To test this hypothesis, we used mouse hepatoma Hepa-1c1c7 cells and their c35 mutant derivative, lacking a functional AHR, to search for candidate kinases that would phosphorylate H3S10 in an AHR dependent manner. Using chromatin immunoprecipitation with antibodies to a comprehensive set of protein kinases, we identified three kinases, IKKα, MSK1 and MSK2, whose binding to the Cyp1a1 enhancer was significantly increased by TCDD in Hepa-1c1c7 cells and absent in control c35 cells. Complexes of AHR, ARNT and IKKα could be co-immunoprecipitated from nuclei of TCDD treated Hepa-1c1c7 cells, and shRNA-mediated IKKα knockdown inhibited both H3S10 phosphorylation in the Cyp1a1 enhancer and the induction of Cyp1a1, Aldh3a1 and Nqo1 in TCDD-treated cells. We conclude that AHR recruits IKKα to the promoter of its target genes and that AHR-mediated H3S10 phosphorylation is a key epigenetic requirement for induction of AHR targets. Given the role of H3S10ph in regulation of chromosome condensation, AHR-IKKα crosstalk may be a mediator of chromatin remodeling by environmental agents.
"Therefore, PR-Set7, but not Riz1, is necessary for repression of specific genes, most likely by monomethylating H4K20. PR-Set7 and Riz1 were also reported to function in gene activation, including the induction of estrogen-responsive genes, suggesting a possible role for the H4K20me1-H3K9me1 trans-tail ‘histone code’ in these pathways (27,28). Although PR-Set7 and Riz1 primarily function in gene repression, further investigation is required to examine their possible function in gene activation. "
[Show abstract][Hide abstract] ABSTRACT: PR-Set7/Set8/KMT5a is the sole histone H4 lysine 20 monomethyltransferase (H4K20me1) in metazoans and is essential for proper cell division and genomic stability. We unexpectedly discovered that normal cellular levels of monomethylated histone H3 lysine 9 (H3K9me1) were also dependent on PR-Set7, but independent of its catalytic activity. This observation suggested that PR-Set7 interacts with an H3K9 monomethyltransferase to establish the previously reported H4K20me1-H3K9me1 trans-tail 'histone code'. Here we show that PR-Set7 specifically and directly binds the C-terminus of the Riz1/PRDM2/KMT8 tumor suppressor and demonstrate that the N-terminal PR/SET domain of Riz1 preferentially monomethylates H3K9. The PR-Set7 binding domain was required for Riz1 nuclear localization and maintenance of the H4K20me1-H3K9me1 trans-tail 'histone code'. Although Riz1 can function as a repressor, Riz1/H3K9me1 was dispensable for the repression of genes regulated by PR-Set7/H4K20me1. Frameshift mutations resulting in a truncated Riz1 incapable of binding PR-Set7 occur frequently in various aggressive cancers. In these cancer cells, expression of wild-type Riz1 restored tumor suppression by decreasing proliferation and increasing apoptosis. These phenotypes were not observed in cells expressing either the Riz1 PR/SET domain or PR-Set7 binding domain indicating that Riz1 methyltransferase activity and PR-Set7 binding domain are both essential for Riz1 tumor suppressor function.
Nucleic Acids Research 01/2014; 42(6). DOI:10.1093/nar/gkt1377 · 9.11 Impact Factor
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