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Nat Commun. 2015 Sep 23;6:8257. doi: 10.1038/ncomms9257.

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

Author information

1
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
3
Department of Surgery, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

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.

PMID:
26394836
PMCID:
PMC4667427
DOI:
10.1038/ncomms9257
[Indexed for MEDLINE]
Free PMC Article

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