Open AccessTCF7L1 suppresses primitive streak gene expression to support human embryonic stem cell pluripotency
Author(s) -
Robert A. Sierra,
Nathan P. Hoverter,
Ricardo N. Ramírez,
Linh Vuong,
A Mortazavi,
Bradley J. Merrill,
Marian L. Waterman,
Peter Donovan
Publication year - 2018
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.161075
Subject(s) - wnt signaling pathway , biology , gastrulation , primitive streak , microbiology and biotechnology , embryonic stem cell , homeobox protein nanog , stem cell , genetics , signal transduction , induced pluripotent stem cell , gene
Human embryonic stem cells (hESCs) are exquisitely sensitive to WNT ligands that 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 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 and not other processes. 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 also find that BMP4, another driver of hESC differentiation, down-regulates TCF7L1, providing a mechanism of BMP and WNT pathway intersection. Together our studies indicate that TCF7L1 plays a major role in maintaining hESCs pluripotency, studies that have implications for human development during gastrulation.