The methyltransferase WHSC1 links transcription elongation to HIRA-mediated histone H3.3 deposition

Friday, November 08, 2013 — Poster Session III
10:00 a.m. – 12:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NICHD	CHROM-8

Authors

N Sarai
K Nimura
T Tamura
T Kanno
MC Patel
T Heightman
K Ura
K Ozato

Abstract

Actively transcribed genes are enriched with the histone variant H3.3. H3.3 deposition into chromatin is associated with transcription-induced nucleosome destabilization and histone exchange. However, mechanisms controlling H3.3 deposition have remained elusive. We investigated the role of the histone methytransferase, Wolf-Hirshhorn syndrome candidate 1 (WHSC1, also known as NSD2 or MMSET) in H3.3 deposition in transcription activated by interferon (IFN). IFN stimulation triggered rapid and prolonged H3.3 incorporation into multiple IFN stimulated genes (ISGs), which accompanied robust ISG mRNA induction in wild type cells. In contrast, H3.3 deposition in ISGs was absent in Whsc1-/- cells, combined with a marked reduction in ISG mRNA induction. Similarly, UV-activated transcription and H3.3 incorporation were both strongly diminished in Whsc1-/- cells. We found that WHSC1 interacted with the bromodomain protein BRD4 and the elongation factor P-TEFb and facilitated transcription elongation. WHSC1 also interacted with HIRA, the H3.3 specific histone chaperone, independently of BRD4 and P-TEFb. WHSC1 and HIRA co-occupied interferon stimulated genes and supported prolonged H3.3 incorporation into activated genes, leaving a lasting transcriptional mark on them. Our results reveal a previously unrecognized role of WHSC1, which links transcription elongation and the H3.3 deposition in activated genes.