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Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells

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Science  26 Jun 2015:
Vol. 348, Issue 6242, pp. 1481-1485
DOI: 10.1126/science.aaa7227

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Keeping quiet one gene at a time

Chromosomal DNA comes in two flavors—euchromatin, which contains most of the expressed genes, and heterochromatin, which usually remains quiet. But what keeps genes within heterochromatin silent? Tchasovnikarova et al. examined the basis for this type of silencing in mammalian cells (see the Perspective by Brummelkamp). They identified a complex of proteins in human cells they called HUSH that kept particular parts of the genome silent by changing associated histone methylation marks.

Science, this issue p. 1481, see also p. 1433

Abstract

Forward genetic screens in Drosophila melanogaster for modifiers of position-effect variegation have revealed the basis of much of our understanding of heterochromatin. We took an analogous approach to identify genes required for epigenetic repression in human cells. A nonlethal forward genetic screen in near-haploid KBM7 cells identified the HUSH (human silencing hub) complex, comprising three poorly characterized proteins, TASOR, MPP8, and periphilin; this complex is absent from Drosophila but is conserved from fish to humans. Loss of HUSH components resulted in decreased H3K9me3 both at endogenous genomic loci and at retroviruses integrated into heterochromatin. Our results suggest that the HUSH complex is recruited to genomic loci rich in H3K9me3, where subsequent recruitment of the methyltransferase SETDB1 is required for further H3K9me3 deposition to maintain transcriptional silencing.

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