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

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 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 HP1γ, inhibits active histone modifications, and attenuates HSP70 promoter activity. Likewise, knockdown of HP1γ leads to the decreased levels of H3.3 in the promoter regions and the repression of HSP70 genes. HP1γ selectively recognizes particular modification states of H3.3 in the nucleosome for its action. Moreover, HP1γ 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 HP1γ make a unique contribution to acute HSP70 transcription and cancer development related to the misregulation of this transcription event.