SUMMARY The recognition of modified histones by “reader” proteins constitutes a key mechanism regulating gene expression in the chromatin context. Compared with the great variety of readers for histone methylation, few protein modules that recognize histone acetylation are known. Here we show that the AF9 YEATS domain binds strongly to histone H3K9 acetylation and, to a lesser extent, H3K27 and H3K18 acetylation. Crystal structural studies revealed that AF9 YEATS adopts an eight-stranded immunoglobin fold and utilizes a serine-lined aromatic “sandwiching” cage for acetyllysine readout, representing a novel recognition mechanism that is distinct from that of known acetyllysine readers. ChIP-seq experiments revealed a strong co-localization of AF9 and H3K9 acetylation genome-wide, which is important for the chromatin recruitment of the H3K79 methyltransferase DOT1L. Together, our studies identified the evolutionarily conserved YEATS domain as a novel acetyllysine-binding module and established a direct link between histone acetylation and DOT1L-mediated H3K79 methylation in transcription control.
Recognition of modified histones by “reader” proteins plays a critical role in the regulation of chromatin1. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions following RNA polymerase II (Pol II) elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state thus suppressing cryptic transcription2. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies3. Here we show that the candidate tumor suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates Pol II elongation. Structural studies reveal that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific “Ser31” residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. ChIP-sequencing analyses reveal a genome-wide colocalization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription corepressor via modulating Pol II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumor cell growth; low expression level of ZMYND11 in breast cancer patients correlates with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumor formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone variant-mediated transcription elongation control to tumor suppression.
SUMMARY The histone lysine demethylase KDM5B regulates gene transcription and cell differentiation. It contains three PHD fingers, the biological roles of which remain elusive. Here, we show that the first PHD1 finger of KDM5B binds unmodified histone H3, whereas the third PHD3 finger prefers the trimethylated mark, H3K4me3. RNA-seq analysis indicates that KDM5B functions as a transcriptional repressor for a set of genes. Biochemical analysis reveals that KDM5B associates with components of the nucleosome remodeling and deacetylase (NuRD) complex and may cooperate with HDAC1 in gene repression. Compared with the estrogen receptor positive breast cancers, KDM5B is downregulated in the triple-negative breast cancer. Overexpression of KDM5B in the MDA-MB 231 breast cancer cells suppresses cell migration and invasion ability, and the PHD1-H3K4me0 interaction is important for inhibition of migration. These findings highlight tumor-suppressive functions of KDM5B in triple-negative breast cancer cells and suggest a novel multivalent mechanism for KDM5B-mediated transcriptional regulation.
Estrogen receptor alpha (ERα) is a ligand-activated transcription factor. Upon estrogen stimulation, ERα recruits a number of coregulators, including both coactivators and corepressors, to the estrogen response elements, modulating gene activation or repression. Most coregulator complexes contain histone-modifying enzymes to control ERα target gene expression in an epigenetic manner. In addition to histones, these epigenetic modifiers can modify nonhistone proteins including ERα, thereby constituting another layer of transcriptional regulation. Here we show that SET and MYND domain containing 2 (SMYD2), a histone H3K4 and H3K36 methyltransferase, directly methylates ERα protein at lysine 266 (K266) both in vitro and in cells. In breast cancer MCF7 cells, SMYD2 attenuates the chromatin recruitment of ERα to prevent ERα target gene activation under an estrogen-depleted condition. Importantly, the SMYD2-mediated repression of ERα target gene expression is mediated by the methylation of ERα at K266 in the nucleus, but not the methylation of histone H3K4. Upon estrogen stimulation, ERα-K266 methylation is diminished, thereby enabling p300/cAMP response element-binding protein-binding protein to acetylate ERα at K266, which is known to promote ERα transactivation activity. Our study identifies a previously undescribed inhibitory methylation event on ERα. Our data suggest that the dynamic cross-talk between SMYD2-mediated ERα protein methylation and p300/cAMP response element-binding protein-binding protein-dependent ERα acetylation plays an important role in fine-tuning the functions of ERα at chromatin and the estrogen-induced gene expression profiles.ERα hinge region | lysine methylation | LSD1 E strogen receptors (ERs) are a subfamily of nuclear receptors that control cellular responses to estrogens (1). There are two different forms of ER, usually referred to as ERα and ERβ, and ERα is the dominant form expressed in breast and ovary tissues. The regulation of hormone-responsive gene expression by ERα as well as other nuclear receptors is a complex process involving a variety of cellular responses. One essential step is the recruitment of transcriptional coregulators-namely, nuclear receptor coactivators (NCOAs; also known as steroid receptor coactivators; e.g., SRC1, 2, and 3) or nuclear receptor corepressors (NCORs)-in a hormone-dependent manner (2). Most coactivator complexes comprise histone lysine (K) acetyltransferases such as p300/cAMP response element-binding protein-binding protein (CBP) (3), which can put on acetylation marks on histones. Histone acetylation helps open up chromatin around the estrogen response element (ERE) regions to facilitate the loading of RNA polymerase II transcriptional machinery. In the absence of its hormone ligands, ERα interacts with corepressor complexes, which normally consist of histone deacetylases (HDACs), to remove acetylation on histones, leading to gene repression (4).In addition to modifying histones, these nuclear receptor coregulators can modify nonhistone proteins, ...
Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.
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