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.
Highlights
Believed to encipher inheritable epigenetic programs that encode distinct nucleosome functions such as gene transcription, X-chromosome inactivation, heterochromatin formation, mitosis, and DNA repair and replication (2– 4)
To gain a comprehensive understanding of the histone modifications associated with ER␣-regulated gene transcription, we first verified the temporal pattern of the recruitment of ER␣ on the promoter of TFF1 (Trefoil factor 1), a well characterized ER␣ target gene, in the estrogen-responsive breast carcinoma cell line MCF-7 by quantitative chromatin immunoprecipitation
H3 serine phosphorylation (H3S10ph) Is Deposited by mitogen- and stress-activated protein kinase 1 (MSK1) in Response to the Activation of MAPK Signaling by E2—In the above ChIP experiment, we found several histone modifications associated with transcription initiation, and our experiments indicated that the increase in the level of H3S10ph was restricted to the TFF1 promoter
Summary
H3K9ac, histone H3 lysine 9 acetylation; H3S10ph, histone H3 serine 10 phosphorylation; H3K4me[3], histone H3 lysine 4 trimethylation; pol II, polymerase II; E2, 17-estradiol; ER␣, estrogen receptor ␣; MSK1, mitogen- and stress-activated protein kinase 1; MAPKBP1, MAPK-binding protein 1; qPCR, quantitative PCR; qChIP, quantitative chromatin immunoprecipitation. Histone Modifications That Govern ER␣-mediated Transcription been implicated in estrogen receptor ␣ (ER␣)-regulated transcription, including SRC-1, CBP/p300, pCAF, G9a, PRMT1, CARM1, and MLL2, all possess chromatin-remodeling capabilities (14 –22). Abundant chromatin modifiers and histone modifications have been described in transcription regulation, including transcription activation by ER␣, how the distinct transcription processes are dictated by histone modifications is not fully understood. We present our analysis of different histone modifications that are associated with distinct processes of ER␣-regulated transcription as well as our identification of the biological effector proteins of several key components of the histone code that governs ER␣-regulated transcription
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