title: Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers.
abstract: Super-enhancers and stretch enhancers (SEs) drive expression of genes that play prominent roles in normal and disease cells, but the functional importance of these clustered enhancer elements is poorly understood, so it is not clear why genes key to cell identity have evolved regulation by such elements. Here, we show that SEs consist of functional constituent units that concentrate multiple developmental signaling pathways at key pluripotency genes in embryonic stem cells and confer enhanced responsiveness to signaling of their associated genes. Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we show that these genes are especially sensitive to perturbation of oncogenic signaling pathways. Super-enhancers thus provide a platform for signaling pathways to regulate genes that control cell identity during development and tumorigenesis.
authors: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors: Denes
authors: D
authors: Hnisz
authors: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors: Jurian
authors: J
authors: Schuijers
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Charles Y
authors: CY
authors: Lin
authors: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors: Abraham S
authors: AS
authors: Weintraub
authors: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors: Brian J
authors: BJ
authors: Abraham
authors: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors: Tong Ihn
authors: TI
authors: Lee
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: James E
authors: JE
authors: Bradner
authors: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: young@wi.mit.edu.
authors: Richard A
authors: RA
authors: Young
mesh_terms: D000818:Animals; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors