SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes

Ken Tajima, Toshifumi Yae, Sarah Javaid, Oliver Tam, Valentine Comaills, Robert Morris, Ben S. Wittner, Mingzhu Liu, Amanda Engstrom, Fumiyuki Takahashi, Joshua C. Black, Sridhar Ramaswamy, Toshihiro Shioda, Molly Hammell, Daniel A. Haber, Johnathan R. Whetstine () and Shyamala Maheswaran ()
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Ken Tajima: Massachusetts General Hospital Cancer Center, Harvard Medical School
Toshifumi Yae: Massachusetts General Hospital Cancer Center, Harvard Medical School
Sarah Javaid: Massachusetts General Hospital Cancer Center, Harvard Medical School
Oliver Tam: Cold Spring Harbor Laboratory
Valentine Comaills: Massachusetts General Hospital Cancer Center, Harvard Medical School
Robert Morris: Massachusetts General Hospital Cancer Center, Harvard Medical School
Ben S. Wittner: Massachusetts General Hospital Cancer Center, Harvard Medical School
Mingzhu Liu: Massachusetts General Hospital Cancer Center, Harvard Medical School
Amanda Engstrom: Massachusetts General Hospital Cancer Center, Harvard Medical School
Fumiyuki Takahashi: Massachusetts General Hospital Cancer Center, Harvard Medical School
Joshua C. Black: Massachusetts General Hospital Cancer Center, Harvard Medical School
Sridhar Ramaswamy: Massachusetts General Hospital Cancer Center, Harvard Medical School
Toshihiro Shioda: Massachusetts General Hospital Cancer Center, Harvard Medical School
Molly Hammell: Cold Spring Harbor Laboratory
Daniel A. Haber: Massachusetts General Hospital Cancer Center, Harvard Medical School
Johnathan R. Whetstine: Massachusetts General Hospital Cancer Center, Harvard Medical School
Shyamala Maheswaran: Massachusetts General Hospital Cancer Center, Harvard Medical School

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: Abstract Expression of the p53-inducible antiproliferative gene BTG2 is suppressed in many cancers in the absence of inactivating gene mutations, suggesting alternative mechanisms of silencing. Using a shRNA screen targeting 43 histone lysine methyltransferases (KMTs), we show that SETD1A suppresses BTG2 expression through its induction of several BTG2-targeting miRNAs. This indirect but highly specific mechanism, by which a chromatin regulator that mediates transcriptional activating marks can lead to the downregulation of a critical effector gene, is shared with multiple genes in the p53 pathway. Through such miRNA-dependent effects, SETD1A regulates cell cycle progression in vitro and modulates tumorigenesis in mouse xenograft models. Together, these observations help explain the remarkably specific genetic consequences associated with alterations in generic chromatin modulators in cancer.

Date: 2015
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DOI: 10.1038/ncomms9257

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