Position-effect variegation revisited: HUSHing up heterochromatin in human cells

Much of what we understand about heterochromatin formation in mammals has been extrapolated from forward genetic screens for modifiers of position-effect variegation (PEV) in the fruit fly Drosophila melanogaster. The recent identification of the HUSH (Human Silencing Hub) complex suggests that more recent evolutionary developments contribute to the mechanisms underlying PEV in human cells. Although HUSH-mediated repression also involves heterochromatin spreading through the reading and writing of the repressive H3K9me3 histone modification, clear orthologues of HUSH subunits are not found in Drosophila but are conserved in vertebrates. Here we compare the insights into the mechanisms of PEV derived from genetic screens in the fly, the mouse and in human cells, review what is currently known about the HUSH complex and discuss the implications of HUSH-mediated silencing for viral latency. Future studies will provide mechanistic insight into HUSH complex function and reveal the relationship between HUSH and other epigenetic silencing complexes.

Chromosomal position-effects have been investigated through Drosophila screens for modifiers of position-effect variegation. An analogous gene-trap mutagenesis screen in near-haploid human KBM7 cells identified HUSH, an epigenetic silencing complex composed of FAM208A/TASOR, MPP8 and Periphilin, which mediates heterochromatin spreading through SETDB1 recruitment and deposition of the repressive H3K9me3 histone modification.

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