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Title: HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development

Abstract

The HAND2 transcriptional regulator controls cardiac development, and we uncover additional essential functions in the endothelial to mesenchymal transition (EMT) underlying cardiac cushion development in the atrioventricular canal (AVC). In Hand2-deficient mouse embryos, the EMT underlying AVC cardiac cushion formation is disrupted, and we combined ChIP-seq of embryonic hearts with transcriptome analysis of wild-type and mutants AVCs to identify the functionally relevant HAND2 target genes. The HAND2 target gene regulatory network (GRN) includes most genes with known functions in EMT processes and AVC cardiac cushion formation. One of these is Snai1, an EMT master regulator whose expression is lost from Hand2-deficient AVCs. Re-expression of Snai1 in mutant AVC explants partially restores this EMT and mesenchymal cell migration. Furthermore, the HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts and other Snai1-expressing tissues. These results show that HAND2 directly regulates the molecular cascades initiating AVC cardiac valve development.

Authors:
 [1];  [1];  [1];  [2];  [3];  [2];  [4];  [1];  [5];  [1];  [1]
  1. Univ. of Basel (Switzerland)
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  3. Univ. of Basel (Switzerland); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  4. The Research Inst. at Nationwide Children’s Hospital, Columbus, OH (United States)
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Univ. of California, Merced, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE
OSTI Identifier:
1379857
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Cell Reports
Additional Journal Information:
Journal Volume: 19; Journal Issue: 8; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Laurent, Frédéric, Girdziusaite, Ausra, Gamart, Julie, Barozzi, Iros, Osterwalder, Marco, Akiyama, Jennifer A., Lincoln, Joy, Lopez-Rios, Javier, Visel, Axel, Zuniga, Aimée, and Zeller, Rolf. HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development. United States: N. p., 2017. Web. doi:10.1016/j.celrep.2017.05.004.
Laurent, Frédéric, Girdziusaite, Ausra, Gamart, Julie, Barozzi, Iros, Osterwalder, Marco, Akiyama, Jennifer A., Lincoln, Joy, Lopez-Rios, Javier, Visel, Axel, Zuniga, Aimée, & Zeller, Rolf. HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development. United States. doi:10.1016/j.celrep.2017.05.004.
Laurent, Frédéric, Girdziusaite, Ausra, Gamart, Julie, Barozzi, Iros, Osterwalder, Marco, Akiyama, Jennifer A., Lincoln, Joy, Lopez-Rios, Javier, Visel, Axel, Zuniga, Aimée, and Zeller, Rolf. Tue . "HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development". United States. doi:10.1016/j.celrep.2017.05.004. https://www.osti.gov/servlets/purl/1379857.
@article{osti_1379857,
title = {HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development},
author = {Laurent, Frédéric and Girdziusaite, Ausra and Gamart, Julie and Barozzi, Iros and Osterwalder, Marco and Akiyama, Jennifer A. and Lincoln, Joy and Lopez-Rios, Javier and Visel, Axel and Zuniga, Aimée and Zeller, Rolf},
abstractNote = {The HAND2 transcriptional regulator controls cardiac development, and we uncover additional essential functions in the endothelial to mesenchymal transition (EMT) underlying cardiac cushion development in the atrioventricular canal (AVC). In Hand2-deficient mouse embryos, the EMT underlying AVC cardiac cushion formation is disrupted, and we combined ChIP-seq of embryonic hearts with transcriptome analysis of wild-type and mutants AVCs to identify the functionally relevant HAND2 target genes. The HAND2 target gene regulatory network (GRN) includes most genes with known functions in EMT processes and AVC cardiac cushion formation. One of these is Snai1, an EMT master regulator whose expression is lost from Hand2-deficient AVCs. Re-expression of Snai1 in mutant AVC explants partially restores this EMT and mesenchymal cell migration. Furthermore, the HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts and other Snai1-expressing tissues. These results show that HAND2 directly regulates the molecular cascades initiating AVC cardiac valve development.},
doi = {10.1016/j.celrep.2017.05.004},
journal = {Cell Reports},
number = 8,
volume = 19,
place = {United States},
year = {Tue May 23 00:00:00 EDT 2017},
month = {Tue May 23 00:00:00 EDT 2017}
}

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