Histone demethylase JMJD2B coordinates H3K4/H3K9 methylation and promotes hormonally responsive breast carcinogenesis

Abstract

It is well-documented that the methylation of histone H3 lysine 4 (H3K4) and of H3K9 are mutually exclusive, an epigenetic phenomenon conserved from yeast to humans. How this opposed methylation modification is accomplished and coordinated in mammalian cells is poorly understood. Here we report that the H3K9 trimethyl demethylase JMJD2B is an integral component of the H3K4-specific methyltransferase, the mixed-lineage leukemia (MLL) 2 complex. We show that the JMJD2B/MLL2 complex is copurified with estrogen receptor α (ERα) and is required for ERα-regulated transcription. We demonstrate that H3K9 demethylation and H3K4 methylation are coordinated in ERα-activated transcription such that H3K9 demethylation is a prerequisite for H3K4 methylation. Significantly, depletion of JMJD2B impairs the estrogen-induced G 1 /S transition of the cell cycle in vitro and inhibits breast tumorigenesis in vivo. Interestingly, JMJD2B itself is an ERα target gene, and forms a feed-forward regulatory loop in regulation of the hormone response. Our results provide a molecular basis for the coordinated H3K4 methylation/H3K9 demethylation in transcription activation, link the trimethyl demethylase JMJD2B to euchromatin functions, and provide a mechanism for JMJD2B in breast carcinogenesis.histone methylation | breast cancer R ecent studies indicate that, analogous to other covalent histone modifications such as acetylation, histone methylation is reversible. However, in contrast to histone acetylation, which is generally associated with active transcription, histone methylation can be associated with either activation or repression of transcription, depending on what effector protein is recruited (1). Even within the same lysine residue, the biological consequences of methylation seem to be variable. For example, methylation of histone H3 lysine 9 (H3K9), long considered a hallmark of heterochromatin (2-8), was recently found to also be present at the transcribed regions of active mammalian genes (9, 10), suggesting that certain methyl marks can have multiple functions in the cell.Given the complexity of histone methylation modification, the integration and/or coordination of methylation/demethylation in a particular biological process becomes an issue of great importance in further understanding the role of histone methylation in nucleosome functioning. Specifically, actively transcribed genes, including the ones that are regulated by estrogen receptor (ER) (11-13), are marked by methylation at histone H3K4, but at the same time by demethylation at H3K9; H3K4 and H3K9 methylation levels are mutually exclusive, and this relationship is conserved from fission yeast to humans. How opposed H3K4 methylation and H3K9 demethylation are achieved and coordinated in transcription activation in mammalian cells is not fully understood.H3K4 methylation is deposited by a family of histone methyltransferases (HMT) that share a conserved SET (Su(var), E(z), and Trithorax) domain. In mammalian cells, multiple HMTs have been characterized: SET1A and SE...

The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1

“…Wissmann and colleagues [41] have demonstrated that JMJD2C, which demethylases H3K9me3, and LSD1, which specifically demethylases H3K9 me2/me1, interact and cooperatively stimulate AR-dependent gene transcription. Recently it has been also reported, in ERa regulated transcription, a coordinated interaction among ERa and the H3K9me3 demethylase JMJD2B, and the H3K4 methyltransferase MLL2 complex has been recently reported [42]. Previous studies have underlined the importance of FAAH in male fertility [18,43], where this hydrolase controls the endogenous levels of AEA, and hence its signaling.…”

Histone demethylase Kdm4b functions as a co-factor of C/EBPβ to promote mitotic clonal expansion during differentiation of 3T3-L1 preadipocytes

“…16,17 Therefore, we hypothesized that Kdm4b might also be involved in regulating MCE during 3T3-L1 preadipocyte differentiation. RNAi oligonucleotide of Kdm4b was transfected into 3T3-L1 preadipocytes.…”

“…Recent studies have shown that Kdm4b is required for estrogen receptor a (ERa)-regulated breast cancer progression and mammary epithelial cells (MECs) proliferation. [16][17][18] In the present study, Kdm4b was identified as a target gene of C/EBPb that functions as a co-factor of C/EBPb to demethylate H3K9me3 in the regulatory regions of C/EBPb-regulated cell cycle genes Cdc45l (cell division cycle 45 homolog), Mcm3 (mini-chromosome maintenance complex component 3), Gins1 (GINS complex subunit 1) and Cdc25c (cell division cycle 25 homolog c), thereby promoting their expression and MCE. This explains why C/EBPb is required for MCE during adipocyte differentiation.…”

Opposing Chromatin Signals Direct and Regulate the Activity of Lysine Demethylase 4C (KDM4C)

“…In principle, the exclusion of colocalized modifications could be explained by a methyltransferase that functions at H3K9 only in the absence of H3K4me3 (or vice versa). Indeed, several H3K9 methyltransferases are partially inhibited by H3K4me3 (16,17), and MLL2, a H3K4 methyltransferase, is similarly inhibited by H3K9me3 (18). Mutual exclusivity could additionally be achieved by demethylases that are selective for H3K9me3 in the presence of H3K4me3 (or vice versa).…”