title: lincRNAs act in the circuitry controlling pluripotency and differentiation.
abstract: Although thousands of large intergenic non-coding RNAs (lincRNAs) have been identified in mammals, few have been functionally characterized, leading to debate about their biological role. To address this, we performed loss-of-function studies on most lincRNAs expressed in mouse embryonic stem (ES) cells and characterized the effects on gene expression. Here we show that knockdown of lincRNAs has major consequences on gene expression patterns, comparable to knockdown of well-known ES cell regulators. Notably, lincRNAs primarily affect gene expression in trans. Knockdown of dozens of lincRNAs causes either exit from the pluripotent state or upregulation of lineage commitment programs. We integrate lincRNAs into the molecular circuitry of ES cells and show that lincRNA genes are regulated by key transcription factors and that lincRNA transcripts bind to multiple chromatin regulatory proteins to affect shared gene expression programs. Together, the results demonstrate that lincRNAs have key roles in the circuitry controlling ES cell state.
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. mguttman@mit.edu
authors.forename: Mitchell
authors.initials: M
authors.lastname: Guttman
authors.forename: Julie
authors.initials: J
authors.lastname: Donaghey
authors.forename: Bryce W
authors.initials: BW
authors.lastname: Carey
authors.forename: Manuel
authors.initials: M
authors.lastname: Garber
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Grenier
authors.forename: Glen
authors.initials: G
authors.lastname: Munson
authors.forename: Geneva
authors.initials: G
authors.lastname: Young
authors.forename: Anne Bergstrom
authors.initials: AB
authors.lastname: Lucas
authors.forename: Robert
authors.initials: R
authors.lastname: Ach
authors.forename: Laurakay
authors.initials: L
authors.lastname: Bruhn
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.forename: John L
authors.initials: JL
authors.lastname: Rinn
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002843:Chromatin; D022661:RNA, Untranslated; D014157:Transcription Factors