Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells
Dawson, Mark A
MetadataShow full item record
Tchasovnikarova, I., Timms, R., Matheson, N., Wals, K., Antrobus, R., Gottgens, B., Dougan, G., et al. (2015). Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science, 348 1481-1485. https://doi.org/10.1126/science.aaa7227
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 non-lethal forward genetic screen in near-haploid KBM7 cells identified the Human Silencing Hub (HUSH), a complex of three poorly-characterised proteins, TASOR, MPP8, and periphilin, which is absent from Drosophila but conserved from fish to humans. Loss of HUSH components resulted in decreased H3K9me3 at both endogenous genomic loci and 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.
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.
Wellcome Trust (101835/Z/13/Z)
Leukaemia & Lymphoma Research (12029)
Wellcome Trust (097922/Z/11/Z)
Leukemia & Lymphoma Society (7001-12)
Cancer Research UK (12765)
Wellcome Trust (100140/Z/12/Z)
External DOI: https://doi.org/10.1126/science.aaa7227
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248418