Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility

JCI Insight. 2023 Mar 8;8(5):e163454. doi: 10.1172/jci.insight.163454.


Based upon our demonstration that the smooth muscle cell-selective (SMC-selective) putative methyltransferase, Prdm6, interacts with myocardin-related transcription factor-A, we examined Prdm6's role in SMCs in vivo using cell type-specific knockout mouse models. Although SMC-specific depletion of Prdm6 in adult mice was well tolerated, Prdm6 depletion in Wnt1-expressing cells during development resulted in perinatal lethality and a completely penetrant patent ductus arteriosus (DA) phenotype. Lineage tracing experiments in Wnt1Cre2 Prdm6fl/fl ROSA26LacZ mice revealed normal neural crest-derived SMC investment of the outflow tract. In contrast, myography measurements on DA segments isolated from E18.5 embryos indicated that Prdm6 depletion significantly reduced DA tone and contractility. RNA-Seq analyses on DA and ascending aorta samples at E18.5 identified a DA-enriched gene program that included many SMC-selective contractile associated proteins that was downregulated by Prdm6 depletion. Chromatin immunoprecipitation-sequencing experiments in outflow tract SMCs demonstrated that 50% of the genes Prdm6 depletion altered contained Prdm6 binding sites. Finally, using several genome-wide data sets, we identified an SMC-selective enhancer within the Prdm6 third intron that exhibited allele-specific activity, providing evidence that rs17149944 may be the causal SNP for a cardiovascular disease GWAS locus identified within the human PRDM6 gene.

Keywords: Cardiovascular disease; Mouse models; Vascular Biology.

Publication types

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

MeSH terms

  • Animals
  • Ductus Arteriosus* / metabolism
  • Ductus Arteriosus, Patent* / genetics
  • Ductus Arteriosus, Patent* / metabolism
  • Female
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Knockout
  • Myocytes, Smooth Muscle / metabolism
  • Pregnancy
  • Repressor Proteins / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Transcription Factors
  • PRDM6, protein, mouse
  • Repressor Proteins