The histone modifications governing TFF1 transcription mediated by estrogen receptor.
ABSTRACT 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.
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ABSTRACT: Trefoil Factor 1 belongs to a group of small secreted proteins (the Trefoil Factor Family proteins), that are localized within the mucous granules and are expressed and secreted by epithelial cells that line mucous membranes. Trefoil Factors are mainly expressed in the gastrointestinal tract, where they normally contribute to maintain the integrity of the mucosa. We recently demonstrated a selective binding ability of Trefoil Factor 1 for copper ions, through its carboxy-terminal tail, and we also observed that copper levels influence the equilibrium between the monomeric and homodimeric forms of Trefoil Factor 1, thus modulating its biological activity. Here we report that transcriptional regulation of Trefoil Factor 1 is also affected by copper levels, through the modulated binding of the copper-sensing transcription factor Sp1 onto the responsive elements present in the regulatory region of the gene. In addition we demonstrate that copper overload causes an accumulation of the trefoil protein in the Trans-Golgi Network and that Trefoil Factor 1 levels can influence copper excretion and copper related toxicity. These findings suggest that the protein might play a role in the overall complex mechanisms of copper homeostasis in the gastrointestinal tissues. Copyright © 2014. Published by Elsevier Ltd.The International Journal of Biochemistry & Cell Biology 12/2014; 59. DOI:10.1016/j.biocel.2014.11.014 · 4.24 Impact Factor
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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.Toxicological Sciences 02/2014; 139(1). DOI:10.1093/toxsci/kfu027 · 4.48 Impact Factor
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ABSTRACT: Histone post-translational modifications impact many aspects of chromatin and nuclear function. Histone H4 Lys 20 methylation (H4K20me) has been implicated in regulating diverse processes ranging from the DNA damage response, mitotic condensation, and DNA replication to gene regulation. PR-Set7/Set8/KMT5a is the sole enzyme that catalyzes monomethylation of H4K20 (H4K20me1). It is required for maintenance of all levels of H4K20me, and, importantly, loss of PR-Set7 is catastrophic for the earliest stages of mouse embryonic development. These findings have placed PR-Set7, H4K20me, and proteins that recognize this modification as central nodes of many important pathways. In this review, we discuss the mechanisms required for regulation of PR-Set7 and H4K20me1 levels and attempt to unravel the many functions attributed to these proteins.Genes & development 02/2012; 26(4):325-37. DOI:10.1101/gad.177444.111 · 12.64 Impact Factor