Repository logo

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

Change log


Tchasovnikarova, Iva A 
Timms, Richard T 
Matheson, Nicholas J 
Wals, Kim 
Antrobus, Robin 


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.



Animals, Antigens, Neoplasm, Chromosomal Position Effects, Conserved Sequence, Drosophila melanogaster, Evolution, Molecular, Gene Silencing, Genes, Reporter, Genetic Loci, Green Fluorescent Proteins, HeLa Cells, Heterochromatin, Histone-Lysine N-Methyltransferase, Histones, Humans, Immunoprecipitation, Multiprotein Complexes, Nuclear Proteins, Phosphoproteins, Protein Methyltransferases

Journal Title


Conference Name

Journal ISSN


Volume Title



American Association for the Advancement of Science (AAAS)
Wellcome Trust (101835/Z/13/Z)
Leukaemia & Lymphoma Research (12029)
Wellcome Trust (097922/Z/11/Z)
Medical Research Council (MC_PC_12009)
Leukemia & Lymphoma Society (7001-12)
Cancer Research Uk (None)
Biotechnology and Biological Sciences Research Council (BB/I00050X/1)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (097922/Z/11/B)
This work was supported by a Wellcome Trust Principal Research Fellowship to P.J.L. (084957/Z/08/Z) and studentship to I.A.T., an MRC Centenary Award to R.T.T., and the Cambridge Biomedical Research Centre (UK). The CIMR is in receipt of a Wellcome Trust Strategic Award.