Analysis of rat cardiac myocytes and fibroblasts identifies combinatorial enhancer organization and transcription factor families

J Mol Cell Cardiol. 2018 Mar;116:91-105. doi: 10.1016/j.yjmcc.2018.02.003. Epub 2018 Feb 5.

Abstract

Cardiac fibroblasts play key roles in both health and disease. Their regulatory elements, transcription factors (TFs), and mechanisms of expression control have not been fully elucidated. We used a differential open chromatin approach, coupled with active enhancer mark, transcriptomic, and computational TFs binding analysis to map cell-type-specific active enhancers in cardiac fibroblasts and cardiomyocytes, and outline the TFs families that control them. This approach was validated by its ability to uncover the known cardiomyocyte TF biology in an unbiased manner, and was then applied to cardiac fibroblasts. We identified Tead, Sox9, Smad, Tcf, Meis, Rbpj, and Runx1 as the main cardiac fibroblasts TF families. Our analysis shows that in both cell types, distal enhancers, containing concentrated combinatorial clusters of multiple tissue expressed TFs recognition motifs, are combinatorically clustered around tissue specific genes. This model for tissue specific gene expression in the heart supports the general "billboard" model for enhancer organization.

Keywords: Cardiac fibroblasts; Enhancers; Genome; Transcription factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Binding Sites
  • Enhancer Elements, Genetic*
  • Fibroblasts / metabolism*
  • Gene Expression Regulation
  • Gene Ontology
  • Gene Regulatory Networks
  • Histones / metabolism
  • Lysine / metabolism
  • Myocytes, Cardiac / metabolism*
  • Nucleotide Motifs / genetics
  • Organ Specificity
  • Promoter Regions, Genetic
  • Protein Binding
  • Rats
  • Transcription Factors / metabolism*
  • Transcription Initiation Site

Substances

  • Histones
  • Transcription Factors
  • Lysine