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TCF7L1 suppresses primitive streak gene expression to support human embryonic stem cell pluripotency.

Authors
  • Sierra, Robert A1
  • Hoverter, Nathan P1
  • Ramirez, Ricardo N2
  • Vuong, Linh M2
  • Mortazavi, Ali2
  • Merrill, Bradley J3
  • Waterman, Marian L4
  • Donovan, Peter J5, 2
  • 1 Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
  • 2 Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
  • 3 Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
  • 4 Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697, USA [email protected] [email protected]
  • 5 Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA [email protected] [email protected]
Type
Published Article
Journal
Development
Publisher
The Company of Biologists
Publication Date
Feb 23, 2018
Volume
145
Issue
4
Identifiers
DOI: 10.1242/dev.161075
PMID: 29361574
Source
Medline
Keywords
License
Unknown

Abstract

Human embryonic stem cells (hESCs) are exquisitely sensitive to WNT ligands, which rapidly cause differentiation. Therefore, hESC self-renewal requires robust mechanisms to keep the cells in a WNT inactive but responsive state. How they achieve this is largely unknown. We explored the role of transcriptional regulators of WNT signaling, the TCF/LEFs. As in mouse ESCs, TCF7L1 is the predominant family member expressed in hESCs. Genome-wide, it binds a gene cohort involved in primitive streak formation at gastrulation, including NODAL, BMP4 and WNT3 Comparing TCF7L1-bound sites with those bound by the WNT signaling effector β-catenin indicates that TCF7L1 acts largely on the WNT signaling pathway. TCF7L1 overlaps less with the pluripotency regulators OCT4 and NANOG than in mouse ESCs. Gain- and loss-of-function studies indicate that TCF7L1 suppresses gene cohorts expressed in the primitive streak. Interestingly, we find that BMP4, another driver of hESC differentiation, downregulates TCF7L1, providing a mechanism of BMP and WNT pathway intersection. Together, our studies indicate that TCF7L1 plays a major role in maintaining hESC pluripotency, which has implications for human development during gastrulation.

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