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 after RNA polymerase 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 tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II elongation. Structural studies show 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 ‘Ser 31’ residue in a composite pocket formed by the tandem bromo–PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a genome-wide co-localization 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 co-repressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumour 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 tumour suppression.
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Gene Expression Omnibus
Protein Data Bank
Structure data have been deposited in Protein Data Bank under accession numbers 4N4G (free bromo–PWWP), 4N4H (bromo–PWWP–H3.1K36me3 complex) and 4N4I (bromo–PWWP–H3.3K36me3 complex). The ChIP-seq and RNA-seq data been deposited in the Gene Expression Omnibus database under accession number GSE48423.
We thank J. Lipsick, Y. Shi, P. Chi, C.D. Allis, D.J. Patel, S.R. Dent, J. Tyler, M. Galko, T. Westbrook, M. Lee, T. Yao and E. Guccione for comments and reagents. We thank the staff at beamlines 1W2B of the Beijing Synchrotron Radiation Facility and BL17U of the Shanghai Synchrotron Radiation Facility for their assistance in data collection. We thank J. Munch for editing the manuscript. This work was supported by grants to X.S. (CPRIT RP110471, Welch G1719, American Cancer Society RSG-13-290-01-TBE, and National institutes of Health (NIH)/MDACC CCSG CA016672), H.L. (The Major State Basic Research Development Program in China, 2011CB965300 and Program for New Century Excellent Talents in University), W.L. (CPRIT RP110471, NIH R01HG007538), B.L. (NIH R01GM090077, Welch I1713), Y.L. (China Postdoctoral Science Foundation, 2012M510413) and H.W. (MD Anderson IRG, Center for Cancer Epigenetics pilot grant). W.L. is a recipient of a Duncan Scholar Award and X.S. is a recipient of a Kimmel Scholar Award.
Extended data figures
Extended data tables
This file contains Supplementary Tables 2-6.