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Histone variant H3.3 stimulates HSP70 transcription through cooperation with HP1?.

ABSTRACT: Histone variant H3.3 and heterochromatin protein 1? (HP1?) are two functional components of chromatin with role in gene transcription. However, the regulations of their dynamics during transcriptional activation and the molecular mechanisms underlying their actions remain poorly understood. Here, we provide evidence that heat shock-induced transcription of the human HSP70 gene is regulated via the coordinated and interdependent action of H3.3 and HP1?. H3.3 and HP1? are rapidly co-enriched at the human HSP70 promoters upon heat shock in a manner that closely parallels the initiation of transcription. Knockdown of H3.3 prevents the stable recruitment of HP1?, inhibits active histone modifications, and attenuates HSP70 promoter activity. Likewise, knockdown of HP1? leads to the decreased levels of H3.3 in the promoter regions and the repression of HSP70 genes. HP1? selectively recognizes particular modification states of H3.3 in the nucleosome for its action. Moreover, HP1? is overexpressed in three representative cancer cell lines, and its knockdown leads to reduction in HSP70 gene transcription and inhibition of cancer cell proliferation. We conclude that the physical and functional interactions between H3.3 and HP1? make a unique contribution to acute HSP70 transcription and cancer development related to the misregulation of this transcription event.

SUBMITTER: Kim H

PROVIDER: S-EPMC3201866 | biostudies-other | 2011 Oct

REPOSITORIES: biostudies-other

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Histone variant H3.3 stimulates HSP70 transcription through cooperation with HP1γ.

Kim Hyunjung H Heo Kyu K Choi Jongkyu J Kim Kyunghwan K An Woojin W

Nucleic acids research 20110708 19

Histone variant H3.3 and heterochromatin protein 1γ (HP1γ) are two functional components of chromatin with role in gene transcription. However, the regulations of their dynamics during transcriptional activation and the molecular mechanisms underlying their actions remain poorly understood. Here, we provide evidence that heat shock-induced transcription of the human HSP70 gene is regulated via the coordinated and interdependent action of H3.3 and HP1γ. H3.3 and HP1γ are rapidly co-enriched at th ...[more]

PMID: 21742762

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Project description:Recognition of modified histones by “reader” proteins plays a critical role in the regulation of transcription1. 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 at an appropriate state to suppress cryptic transcription2,3. 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 bodies4. 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 analysis 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 the transition of the promoter-proximal paused Pol II to elongation. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumor cell growth; higher expression of ZMYND11 is observed in triple-negative breast cancer patients with better prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth 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. ChIP-seq analysis of ZMYND11, H3K36me3 in U2OS cells and ZMYND11 knockdown cells; ChIP-seq of H3.3 in Flag-H3.3 stable U2OS cells; RNA-seq of ZNYMD11 depleted U2OS cells.

Dataset Information

Histone variant H3.3 stimulates HSP70 transcription through cooperation with HP1?.

Publications

Histone variant H3.3 stimulates HSP70 transcription through cooperation with HP1γ.

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