George, Rajani M; Firulli, Beth A; Podicheti, Ram; Rusch, Douglas B; Mannion, Brandon J; Pennacchio, Len A; Osterwalder, Marco; Firulli, Anthony B (2023). Single cell evaluation of endocardial HAND2 gene regulatory networks reveals critical HAND2 dependent pathways impacting cardiac morphogenesis. Development, 150(3) The Company of Biologists 10.1242/dev.201341
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The transcription factor HAND2 plays critical roles during cardiogenesis. Hand2 endocardial deletion (H2CKO) results in tricuspid atresia or double inlet left ventricle with accompanying intraventricular septum defects, hypo-trabeculated ventricles, and an increased density of coronary lumens. To understand the regulatory mechanisms of these phenotypes, single cell transcriptome analysis of E11.5 H2CKO hearts was performed revealing a number of disrupted endocardial regulatory pathways. Utilizing HAND2 DNA occupancy data, we identify several HAND2-dependent enhancers, including two endothelial enhancers for the shear-stress master regulator, KLF2. A 1.8kb enhancer located 50kb upstream of the Klf2 TSS imparts specific endothelial/endocardial expression within the vasculature and endocardium. This enhancer is HAND2-dependent for ventricular endocardium expression but HAND2-independent for Klf2 vascular and valve expression. Deletion of this Klf2 enhancer results in reduced Klf2 expression within ventricular endocardium. These data reveal that HAND2 functions within endocardial gene regulatory networks including shear-stress response.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Kardiologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Kardiologie |
UniBE Contributor: |
Osterwalder, Marco |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1477-9129 |
Publisher: |
The Company of Biologists |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
12 Jan 2023 10:34 |
Last Modified: |
11 Jan 2024 00:25 |
Publisher DOI: |
10.1242/dev.201341 |
PubMed ID: |
36620995 |
Uncontrolled Keywords: |
Cardiogenesis Congenital heart defects Endocardial development HAND factors |
BORIS DOI: |
10.48350/177121 |
URI: |
https://boris.unibe.ch/id/eprint/177121 |
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