DIGIT Is a Conserved Long Noncoding RNA that Regulates GSC Expression to Control Definitive Endoderm Differentiation of Embryonic Stem Cells

Kaveh Daneshvar; Joshua V. Pondick; Byeong-Moo Kim; Chan Zhou; Samuel R. York; Jillian A. Macklin; Ameed Abualteen; Bo Tan; Alla A. Sigova; Chelsea Marcho; Kimberly D. Tremblay; Jesse Mager; Michael Y. Choi; Alan C. Mullen

doi:10.1016/j.celrep.2016.09.017

Cell Reports (Oct 2016)

DIGIT Is a Conserved Long Noncoding RNA that Regulates GSC Expression to Control Definitive Endoderm Differentiation of Embryonic Stem Cells

Kaveh Daneshvar,
Joshua V. Pondick,
Byeong-Moo Kim,
Chan Zhou,
Samuel R. York,
Jillian A. Macklin,
Ameed Abualteen,
Bo Tan,
Alla A. Sigova,
Chelsea Marcho,
Kimberly D. Tremblay,
Jesse Mager,
Michael Y. Choi,
Alan C. Mullen

Affiliations

Kaveh Daneshvar: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Joshua V. Pondick: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Byeong-Moo Kim: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Chan Zhou: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Samuel R. York: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Jillian A. Macklin: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Ameed Abualteen: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Bo Tan: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Alla A. Sigova: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Chelsea Marcho: Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, MA 01003, USA
Kimberly D. Tremblay: Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, MA 01003, USA
Jesse Mager: Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, MA 01003, USA
Michael Y. Choi: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Alan C. Mullen: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA

DOI: https://doi.org/10.1016/j.celrep.2016.09.017
Journal volume & issue: Vol. 17, no. 2
pp. 353 – 365

Abstract

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Long noncoding RNAs (lncRNAs) exhibit diverse functions, including regulation of development. Here, we combine genome-wide mapping of SMAD3 occupancy with expression analysis to identify lncRNAs induced by activin signaling during endoderm differentiation of human embryonic stem cells (hESCs). We find that DIGIT is divergent to Goosecoid (GSC) and expressed during endoderm differentiation. Deletion of the SMAD3-occupied enhancer proximal to DIGIT inhibits DIGIT and GSC expression and definitive endoderm differentiation. Disruption of the gene encoding DIGIT and depletion of the DIGIT transcript reveal that DIGIT is required for definitive endoderm differentiation. In addition, we identify the mouse ortholog of DIGIT and show that it is expressed during development and promotes definitive endoderm differentiation of mouse ESCs. DIGIT regulates GSC in trans, and activation of endogenous GSC expression is sufficient to rescue definitive endoderm differentiation in DIGIT-deficient hESCs. Our study defines DIGIT as a conserved noncoding developmental regulator of definitive endoderm.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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