ETV2 primes hematoendothelial gene enhancers prior to hematoendothelial fate commitment

Jeffrey D Steimle; Chul Kim; Megan Rowton; Rangarajan D Nadadur; Zhezhen Wang; Matthew Stocker; Andrew D Hoffmann; Erika Hanson; Junghun Kweon; Tanvi Sinha; Kyunghee Choi; Brian L Black; John M Cunningham; Ivan P Moskowitz; Kohta Ikegami

doi:10.1016/j.celrep.2023.112665

ETV2 primes hematoendothelial gene enhancers prior to hematoendothelial fate commitment

Cell Rep. 2023 Jun 27;42(6):112665. doi: 10.1016/j.celrep.2023.112665. Epub 2023 Jun 17.

Authors

Affiliations

¹ Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA.
² Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA; Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
³ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁵ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
⁷ Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
⁸ Division of Molecular and Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA. Electronic address: [email protected].

Abstract

Mechanisms underlying distinct specification, commitment, and differentiation phases of cell fate determination remain undefined due to difficulties capturing these processes. Here, we interrogate the activity of ETV2, a transcription factor necessary and sufficient for hematoendothelial differentiation, within isolated fate intermediates. We observe transcriptional upregulation of Etv2 and opening of ETV2-binding sites, indicating new ETV2 binding, in a common cardiac-hematoendothelial progenitor population. Accessible ETV2-binding sites are active at the Etv2 locus but not at other hematoendothelial regulator genes. Hematoendothelial commitment coincides with the activation of a small repertoire of previously accessible ETV2-binding sites at hematoendothelial regulators. Hematoendothelial differentiation accompanies activation of a large repertoire of new ETV2-binding sites and upregulation of hematopoietic and endothelial gene regulatory networks. This work distinguishes specification, commitment, and sublineage differentiation phases of ETV2-dependent transcription and suggests that the shift from ETV2 binding to ETV2-bound enhancer activation, not ETV2 binding to target enhancers, drives hematoendothelial fate commitment.

Keywords: CP: Molecular biology; CP: Stem cell research; ETV2; VEGF; cell fate; commitment; differentiation; endothelial development; hematoendothelium; hematopoiesis; pioneer factors; transcriptional regulation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation / genetics
Endothelium / metabolism
Gene Expression Regulation, Developmental
Hematopoietic Stem Cells* / metabolism
Regulatory Sequences, Nucleic Acid
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

Transcription Factors
ETV2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding