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Poleshko A , Kossenkov AV , Shalginskikh N , Pecherskaya A , Einarson MB , Marie Skalka A , Katz RA
Human factors and pathways essential for mediating epigenetic gene silencing
Epigenetics. 2014 Sep;9(9) :1280-9
PMID: 25147916   
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Cellular identity in both normal and disease processes is determined by programmed epigenetic activation or silencing of specific gene subsets. Here, we have used human cells harboring epigenetically silent GFP-reporter genes to perform a genome-wide siRNA knockdown screen for the identification of cellular factors that are required to maintain epigenetic gene silencing. This unbiased screen interrogated 21,121 genes, and we identified and validated a set of 128 protein factors. This set showed enrichment for functional categories, and protein-protein interactions. Among this set were known epigenetic silencing factors, factors with no previously identified role in epigenetic gene silencing, as well as unstudied factors. The set included non-nuclear factors, for example, components of the integrin-adhesome. A key finding was that the E1 and E2 enzymes of the small ubiquitin-like modifier (SUMO) pathway (SAE1, SAE2/UBA2, UBC9/UBE2I) are essential for maintenance of epigenetic silencing. This work provides the first genome-wide functional view of human factors that mediate epigenetic gene silencing. The screen output identifies novel epigenetic factors, networks, and mechanisms, and provides a set of candidate targets for epigenetic therapy and cellular reprogramming.
1559-2308 Poleshko, Andrey Kossenkov, Andrew V Shalginskikh, Natalia Pecherskaya, Anna Einarson, Margret B Marie Skalka, Anna Katz, Richard A CA006927/CA/NCI NIH HHS/United States CA071515/CA/NCI NIH HHS/United States DK082498/DK/NIDDK NIH HHS/United States R01 CA071515/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States Epigenetics. 2014 Sep;9(9):1280-9. doi: 10.4161/epi.32088. Epub 2014 Aug 4.