Cited by 1Genomics and Chromatin DynamicsDevelopmental Biology and Gene RegulationPluripotent Stem Cells Research

TBX3 advances the developmental chromatin landscape toward the hepatic fate

Open access
Stephan, Tabea L., Cullum, Rebecca, Drissler, Sibyl, Thomas, Ashleigh, Fuglerud, Bettina M., Clement-Ranney, Makenna, Lotto, Jeremy, Krentz, Nicole A.J. +2 more·2025·Developmental Cell

Abstract

By mapping histone modifications in a human stem cell model of hepatic differentiation, we identified an enhancer landscape that is dynamic and stage specific, with many primed at the definitive endoderm stage. While hepatic enhancers gained active histone modifications, non-hepatic enhancers lost H3K4me1 after hepatic specification. T-box transcription factor 3 (TBX3) was found to bind to hepatic enhancers and promoters. TBX3 binding was transient, and only upon the dissociation of TBX3 from its bound regions were active histone modifications acquired. Subsequently, transcription was activated, supporting a role for TBX3 in directly activating the hepatic lineage. Constitutive overexpression of TBX3 indicated that dissociation of TBX3 is crucial for gene activation. TBX3 did not bind to any pancreatic regulatory regions directly, indicating indirect repression of the pancreatic lineage. Together, this suggests that TBX3 plays a role in identifying and bookmarking hepatic enhancers and promoters during specification, which subsequently will be activated to drive cell identity.

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Crossref · 10.1016/j.devcel.2025.05.014

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Authors
Stephan, T. L., Cullum, R., Drissler, S., Thomas, A., Fuglerud, B. M., Clement-Ranney, M., Lotto, J., Krentz, N. A. J., Duncan, S. A., & Hoodless, P. A.
Affiliations
  • University of British Columbia (CA)
  • Medical University of South Carolina (US)
Corresponding author
Hoodless, Pamela A.
Venue
Developmental Cell
Publisher
Elsevier BV
Published
2025-10
Volume
60
Issue
19
Pages
2679-2694.e5
ISSN
1534-5807 (ISSN-L)
OpenAlex
W4411412401
Cited by
1
References
59
Citations by year
2026: 1
FWCI
0.26
Type
journal article
Language
en
Open access
Locations
  • Developmental Cell (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Canadian Institutes of Health Research (FRN153006, FRN183794, FRN128092)
  • University of British Columbia
  • Natural Sciences and Engineering Research Council of Canada
  • Genome British Columbia
  • Norges Forskningsråd (FRIPRO 275783)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
TBX3, hepatic differentiation, histone modifications, enhancers, H3K4me1, definitive endoderm, transcriptional activation, T-box transcription factor, cell fate specification, stem cell differentiation, chromatin landscape
MeSH terms
Cell Differentiation, Chromatin, Endoderm, Enhancer Elements, Genetic, Histones, Humans, Liver, Promoter Regions, Genetic, Gene Expression Regulation, Developmental, Cell Lineage, T-Box Domain Proteins

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