SETDB1/HUSH modulates Xist RNA levels during establishment of X chromosome inactivation [RNA-Seq]

Prior studies have determined that Xist transcription and turnover are modulated to maintain the correct level of Xist RNA to inactivate a single X chromosome. The underlying molecular mechanisms are poorly understood.

In this study we demonstrate that RNA-dependent recruitment of the H3K9me3 methyltransferase SETDB1 and the HUSH complex across the transcribed Xist locus functions to suppress Xist transcription during establishment of XCI. Thus, degron-mediated acute depletion of SETDB1 or core HUSH subunits abrogates allelic H3K9me3 deposition, increasing Xist transcription, accumulation of Xist RNA, and the rate of X chromosome gene silencing.