ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression

Abstract

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.

Histone Variant H3.3: A versatile H3 variant in health and in disease

“…In another study, BS69/ZMYND11 was reported to regulate transcription elongation via its recognition of H3K36me3 on H3.3. Thus it repressed transcriptional programs essential for tumor proliferation (Wen et al, 2014c). The K36M mutation has been found in H3F3B at high prevalence in Chondroblastoma, and was reported to abolish H3K36me3 modification when introduced in 293T cells.…”

“…Several proteins have been reported to read H3K36me3 modifications by virtue of possessing a PWWP domain, including DNMT3a and Brpf1 (Dhayalan et al, 2010;Vezzoli et al, 2010;Wu et al, 2011). A recent report described for the first time, a reader for H3.3-specific K36me3 called BS69/ZMYND11 (Wen et al, 2014c). BS69 has been identified as a tumor suppressor, as it inhibits transcriptional activation regulated by E1A and c-Myb (Hateboer et al, 1995;Ladendorff et al, 2001).…”

Histone H3.3 and cancer: A potential reader connection

“…In both studies, the authors used an array of methylated and unmethylated histone peptides and demonstrated that, surprisingly, BS69 preferentially recognizes H3.3K36me3. This highly specific recognition is sensitive to both the methyl level on lysine 36: i.e., BS69 binds to H3.3K36me3, but much less to H3.3K36me0/1/2, as well as the adjacent residues, S31 on H3.3 vs. A31 on H3.1/2 (23,24). Using a cocrystallization approach, the Wen et al study provided at the atomic level mechanistic understanding of how the BS69 reader modalities discriminate H3.3K36me3 from H3.1K36me3.…”

“…In these two recent studies (23,24), the BS69 PWWP domain was identified as a specific reader for the K36 trimethylation on histone variant H3.3 (H3.3K36me3) (Fig. 1).…”

“…provide a new avenue to explore H3.3 biology as well as its cancer connection (23,24). BS69 (also Known as ZMYND11) BS69 was originally identified as an interacting protein of the adenoviral E1A oncoprotein and a suppressor of the transactivating function of E1A and has thus been suggested to function as a transcriptional repressor and a candidate tumor suppressor (25)(26)(27).…”