PUBLICATION

HDAC1-mediated repression of the retinoic acid-responsive gene ripply3 promotes second heart field development

Authors
Song, Y.C., Dohn, T.E., Rydeen, A.B., Nechiporuk, A.V., Waxman, J.S.
ID
ZDB-PUB-190516-21
Date
2019
Source
PLoS Genetics   15: e1008165 (Journal)
Registered Authors
Nechiporuk, Alex, Waxman, Joshua
Keywords
none
Datasets
GEO:GSE126747
MeSH Terms
  • Animals
  • Cell Differentiation/genetics
  • Gene Expression Regulation, Developmental/genetics
  • Heart/physiology
  • Heart Ventricles/metabolism
  • Histone Deacetylase 1/genetics*
  • Histone Deacetylase 1/metabolism*
  • Myocytes, Cardiac/physiology
  • Organogenesis
  • Repressor Proteins/metabolism
  • Stem Cells/metabolism
  • Transcription Factors/metabolism
  • Tretinoin/metabolism
  • Ventricular Function/genetics*
  • Ventricular Function/physiology
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism*
PubMed
31091225 Full text @ PLoS Genet.
Abstract
Coordinated transcriptional and epigenetic mechanisms that direct development of the later differentiating second heart field (SHF) progenitors remain largely unknown. Here, we show that a novel zebrafish histone deacetylase 1 (hdac1) mutant allele cardiac really gone (crg) has a deficit of ventricular CMs and smooth muscle within the outflow tract (OFT) due to both cell and non-cell autonomous loss in SHF progenitor proliferation. Cyp26-deficient embryos, which have increased retinoic acid (RA) levels, have similar defects in SHF-derived OFT development. We found that nkx2.5+ progenitors from Hdac1 and Cyp26-deficient embryos have ectopic expression of ripply3, a transcriptional co-repressor of T-box transcription factors that is normally restricted to the posterior pharyngeal endoderm. Furthermore, the ripply3 expression domain is expanded anteriorly into the posterior nkx2.5+ progenitor domain in crg mutants. Importantly, excess ripply3 is sufficient to repress VC development, while genetic depletion of Ripply3 and Tbx1 in crg mutants can partially restore VC number. We find that the epigenetic signature at RA response elements (RAREs) that can associate with Hdac1 and RA receptors (RARs) becomes indicative of transcriptional activation in crg mutants. Our study highlights that transcriptional repression via the epigenetic regulator Hdac1 facilitates OFT development through directly preventing expression of the RA-responsive gene ripply3 within SHF progenitors.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes