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...
Maintenance of genomic stability is essential for normal organismal development and is vital to prevent diseases such as cancer. As genetic information is packaged into chromatin, it has become increasingly clear that the chromatin environment plays an important role in DNA damage response. However, how DNA repair is controlled by epigenetic mechanisms is not fully understood. Here we report the identification and characterization of lysine-specific histone demethylase 5B (KDM5B), a member of the JmjC domaincontaining histone demethylases, as an important player in multiple aspects of DNA double-strand break (DSB) response in human cells. We found that KDM5B becomes enriched in DNA-damage sites after ironizing radiation and endonuclease treatment in a poly(ADP ribose) polymerase 1-and histone variant macroH2A1.1-dependent manner. We showed that KDM5B is required for efficient DSB repair and for the recruitment of Ku70 and BRCA1, the essential component of nonhomologous end-joining and homologous recombination, respectively. Significantly, KDM5B deficiency disengages the DNA repair process, promotes spontaneous DNA damage, activates p53 signaling, and sensitizes cells to genotoxic insults. Our results suggest that KDM5B is a bona fide DNA damage response protein and indicate that KDM5B is an important genome caretaker and a critical regulator of genome stability, adding to the understanding of the roles of epigenetics in the maintenance of genetic fidelity.chromatin modification | histone methylation | genome maintenance T he ability of cells to maintain genome integrity is vital for cellular homeostasis. Defects in the maintenance of genome stability underlie a number of developmental disorders and human diseases including cancer (1-3). Compared with other types of DNA lesions, DNA double-strand breaks (DSBs) are particularly dangerous to cells because failure to repair these kinds of damage in an appropriate manner can cause cell death, and aberrant repair can lead to gross chromosomal abnormalities that may eventually lead to tumorigenesis (1, 2, 4).Upon detection of DSBs, cells activate local and global DNA damage response (DDR) events that promote cell-cycle checkpoint activation and DNA repair signaling (5, 6). For example, in response to DSBs, phosphorylation of the histone variant H2AX (γH2AX) by DDR protein kinases such as ataxia telangiectasia mutated (ATM) (7) creates an extensive modified chromatin environment that allows spatiotemporal redistribution and accumulation of checkpoint and repair factors, including DNAdamage check point-1 (MDC1) and breast cancer susceptibility gene 1 (BRCA1), into repair centers, forming microscopically visible nuclear aggregates known as foci (4, 8). The two extensively studied DSB repair pathways are homologous recombination (HR) and nonhomologous end-joining (NHEJ) (2, 9). In NHEJ, the DSB ends are blocked from 5′ end resection and held in a close proximity by DSB end-binding protein complex, the Ku70-Ku80 heterodimer (10). NHEJ promotes direct ligation of the DSB end...
How loss-of-function of GATA3 contributes to the development of breast cancer is poorly understood. Here, we report that GATA3 nucleates a transcription repression program composed of G9A and MTA3-, but not MTA1- or MTA2-, constituted NuRD complex. Genome-wide analysis of the GATA3/G9A/NuRD(MTA3) targets identified a cohort of genes including ZEB2 that are critically involved in epithelial-to-mesenchymal transition and cell invasion. We demonstrate that the GATA3/G9A/NuRD(MTA3) complex inhibits the invasive potential of breast cancer cells in vitro and suppresses breast cancer metastasis in vivo. Strikingly, the expression of GATA3, G9A, and MTA3 is concurrently downregulated during breast cancer progression, leading to an elevated expression of ZEB2, which, in turn, represses the expression of G9A and MTA3 through the recruitment of G9A/NuRD(MTA1).
Although clinically associated with severe developmental defects, the biological function of FOXK2 remains poorly explored. Here we report that FOXK2 interacts with transcription corepressor complexes NCoR/SMRT, SIN3A, NuRD, and REST/CoREST to repress a cohort of genes including HIF1β and EZH2 and to regulate several signaling pathways including the hypoxic response. We show that FOXK2 inhibits the proliferation and invasion of breast cancer cells and suppresses the growth and metastasis of breast cancer. Interestingly, FOXK2 is transactivated by ERα and transrepressed via reciprocal successive feedback by HIF1β/EZH2. Significantly, the expression of FOXK2 is progressively lost during breast cancer progression, and low FOXK2 expression is strongly correlated with higher histologic grades, positive lymph nodes, and ERα/PR/HER2 status, all indicators of poor prognosis.
Background: TDP-43 is a major pathological hallmark of several neurodegenerative diseases. Results: TDP-43 interacts with FMRP/STAU1 and binds to the 3Ј-UTR of SIRT1 mRNA to promote its stability. Conclusion: TDP-43, FMRP, and STAU1 form a functionally coordinated complex to regulate the expression of SIRT1. Significance: Adding to our understanding of the mechanistic role of TDP-43 in neurodegenerative diseases.
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