Dynamic chromatin organization and regulatory interactions in human endothelial cell differentiation

Kris G Alavattam; Katie A Mitzelfelt; Giancarlo Bonora; Paul A Fields; Xiulan Yang; Han Sheng Chiu; Lil Pabon; Alessandro Bertero; Nathan J Palpant; William S Noble; Charles E Murry

doi:10.1016/j.stemcr.2022.11.003

Dynamic chromatin organization and regulatory interactions in human endothelial cell differentiation

Stem Cell Reports. 2023 Jan 10;18(1):159-174. doi: 10.1016/j.stemcr.2022.11.003. Epub 2022 Dec 8.

Authors

Affiliations

¹ Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, William H. Foege Hall, 3720 15th Avenue NE, Seattle, WA 98195, USA.
² Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA.
³ Department of Genome Sciences, University of Washington, William H. Foege Hall, 3720 15th Avenue NE, Seattle, WA 98195, USA.
⁴ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; Centre for Cardiac and Vascular Biology, The University of Queensland, Brisbane, QLD 4072, Australia.
⁵ Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA; Sana Biotechnology, Seattle, WA 98102, USA.
⁶ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; Centre for Cardiac and Vascular Biology, The University of Queensland, Brisbane, QLD 4072, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
⁷ Department of Genome Sciences, University of Washington, William H. Foege Hall, 3720 15th Avenue NE, Seattle, WA 98195, USA; Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA 98195, USA. Electronic address: wnoble@uw.edu.
⁸ Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA; Sana Biotechnology, Seattle, WA 98102, USA; Department of Medicine/Cardiology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Department of Bioengineering, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA. Electronic address: murry@uw.edu.

Abstract

Vascular endothelial cells are a mesoderm-derived lineage with many essential functions, including angiogenesis and coagulation. The gene-regulatory mechanisms underpinning endothelial specialization are largely unknown, as are the roles of chromatin organization in regulating endothelial cell transcription. To investigate the relationships between chromatin organization and gene expression, we induced endothelial cell differentiation from human pluripotent stem cells and performed Hi-C and RNA-sequencing assays at specific time points. Long-range intrachromosomal contacts increase over the course of differentiation, accompanied by widespread heteroeuchromatic compartment transitions that are tightly associated with transcription. Dynamic topologically associating domain boundaries strengthen and converge on an endothelial cell state, and function to regulate gene expression. Chromatin pairwise point interactions (DNA loops) increase in frequency during differentiation and are linked to the expression of genes essential to vascular biology. Chromatin dynamics guide transcription in endothelial cell development and promote the divergence of endothelial cells from cardiomyocytes.

Keywords: cardiomyocytes; chromatin; differentiation; endothelium; genome organization; transcription.

Publication types

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

MeSH terms

Cell Differentiation / genetics
Chromatin*
Endothelial Cells*
Gene Expression Regulation
Humans

Substances

Chromatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding