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

Yuntao Charlie Song, Tracy E. Dohn, Ariel B. Rydeen, Alex Nechiporuk, Joshua S. Waxman

Research output: Contribution to journalArticle

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 cardiomyocytes (VCs) and smooth muscle within the outflow tract (OFT) due to both cell and non-cell autonomous loss in SHF progenitor proliferation. Cyp26deficient 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 Tbox 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.

Original languageEnglish (US)
Article numbere1008165
JournalPLoS genetics
Volume15
Issue number5
DOIs
StatePublished - May 1 2019

Fingerprint

retinoic acid
Tretinoin
heart
Cardiac Myocytes
epigenetics
mutants
outflow
gene
acid
Epigenomics
Genes
embryo
Epigenetic Repression
embryo (animal)
genes
Embryonic Structures
Co-Repressor Proteins
histone deacetylase
Endoderm
Retinoic Acid Receptors

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

HDAC1-mediated repression of the retinoic acid-responsive gene ripply3 promotes second heart field development. / Song, Yuntao Charlie; Dohn, Tracy E.; Rydeen, Ariel B.; Nechiporuk, Alex; Waxman, Joshua S.

In: PLoS genetics, Vol. 15, No. 5, e1008165, 01.05.2019.

Research output: Contribution to journalArticle

Song, Yuntao Charlie ; Dohn, Tracy E. ; Rydeen, Ariel B. ; Nechiporuk, Alex ; Waxman, Joshua S. / HDAC1-mediated repression of the retinoic acid-responsive gene ripply3 promotes second heart field development. In: PLoS genetics. 2019 ; Vol. 15, No. 5.
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