Cyclin D1 integrates G9a-mediated histone methylation

Iouri Chepelev,Adam Ertel,D V Klopfenstein,Mathew C Casimiro,William Dampier,Xiaoming Ju,Sanjay Katiyar,Albert Jeltsch,Xuanmao Jiao,Richard G Pestell,Aydin Tozeren,Zhiping Li,Min Wang,Gabriele Di Sante

doi:10.1038/s41388-019-0723-8

Abstract

Lysine methylation of histones and non-histone substrates by the SET domain containing protein lysine methyltransferase (KMT) G9a/EHMT2 governs transcription contributing to apoptosis, aberrant cell growth, and pluripotency. The positioning of chromosomes within the nuclear three-dimensional space involves interactions between nuclear lamina (NL) and the lamina-associated domains (LAD). Contact of individual LADs with the NL are dependent upon H3K9me2 introduced by G9a. The mechanisms governing the recruitment of G9a to distinct subcellular sites, into chromatin or to LAD, is not known. The cyclin D1 gene product encodes the regulatory subunit of the holoenzyme that phosphorylates pRB and NRF1 thereby governing cell-cycle progression and mitochondrial metabolism. Herein, we show that cyclin D1 enhanced H3K9 dimethylation though direct association with G9a. Endogenous cyclin D1 was required for the recruitment of G9a to target genes in chromatin, for G9a-induced H3K9me2 of histones, and for NL-LAD interaction. The finding that cyclin D1 is required for recruitment of G9a to target genes in chromatin and for H3K9 dimethylation, identifies a novel mechanism coordinating protein methylation.

Highlights

Histone methylation is dynamically regulated by histone methyltransferases (HKMTs) and histone lysine demethylases [1]
In order to determine whether the induction of H3K9me2 at specific chromatin elements by cyclin D1 involved association of cyclin D1 with G9a, immuneprecipitation was conducted of endogenous cyclin D1 in the human MCF-7 breast cancer cell line
The current studies define novel functions for cyclin D1 determined through binding of the protein methyltransferase G9a

Summary

Introduction

Histone methylation is dynamically regulated by histone methyltransferases (HKMTs) and histone lysine demethylases [1]. The Su(var) 3-9-Enhancer of zeste-Trithorax (SET) domain of Suv39h1/ KMT1a encodes the catalytic domain, which governs lysine methylation [2]. Both Suv39h1 and G9a catalyze mono-, di-, and tri-methylation reactions on H3K9 [3, 4]. G9a associates with heterochromatin protein 1 (HP1) to regulate chromatin binding and association with methylated histones [6]. Distinct domains of G9a, including the Cys-rich region (CYS), the ankyrin repeat (ANK), and the SET domain, facilitate interactions with either methylated histones or associated proteins. The association of the multi H3K9 methyl-binding protein modules, which includes HP1 and G9a, may result in the spreading of H3K9me marks [9]. The non-histone substrates of G9a include p53, Wiz, CDYL1, ACINUS, and Reptin [10,11,12,13]

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Results

Conclusion