title: SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes.
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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Tajima
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yae
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Javaid
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Oliver
authors.identifier: http://orcid.org/0000-0002-1023-3655
authors.initials: O
authors.lastname: Tam
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Valentine
authors.initials: V
authors.lastname: Comaills
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Morris
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Ben S
authors.identifier: http://orcid.org/0000-0001-5657-9849
authors.initials: BS
authors.lastname: Wittner
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Liu
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Engstrom
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Takahashi
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Black
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Shioda
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Hammell
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Surgery, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D009374:Neoplasms, Experimental; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D017874:Immediate-Early Proteins; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human; D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human