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

[wolf-hirschhorn syndrome]

Actively transcribed genes are enriched with the histone variant H 3 .3 . Although H 3 .3 deposition has been linked to transcription , mechanisms controlling this process remain elusive . We investigated the role of the histone methyltransferase Wolf-Hirschhorn syndrome candidate 1 (WHSC 1 ) (NSD 2 /MMSET ) in H 3 .3 deposition into interferon (IFN ) response genes . IFN treatment triggered robust H 3 .3 incorporation into activated genes , which continued even after cessation of transcription . Likewise , UV radiation caused H 3 .3 deposition in UV-activated genes . However , in Whsc 1 (-/-) cells IFN- or UV-triggered H 3 .3 deposition was absent , along with a marked reduction in IFN- or UV-induced transcription . We found that WHSC 1 interacted with the bromodomain protein 4 (BRD 4 ) and the positive transcription elongation factor b (P-TEFb ) and facilitated transcriptional elongation . WHSC 1 also associated with HIRA , the H 3 .3 -specific histone chaperone , independent of BRD 4 and P-TEFb . WHSC 1 and HIRA co -occupied IFN-stimulated genes and supported prolonged H 3 .3 incorporation , leaving a lasting transcriptional mark . Our results reveal a previously unrecognized role of WHSC 1 , which links transcriptional elongation and H 3 .3 deposition into activated genes through two molecularly distinct pathways .