Pax3 cooperates with Ldb1 to direct local chromosome architecture during myogenic lineage specification

Nat Commun. 2019 May 24;10(1):2316. doi: 10.1038/s41467-019-10318-6.

Abstract

Chromatin looping allows enhancer-bound regulatory factors to influence transcription. Large domains, referred to as topologically associated domains, participate in genome organization. However, the mechanisms underlining interactions within these domains, which control gene expression, are not fully understood. Here we report that activation of embryonic myogenesis is associated with establishment of long-range chromatin interactions centered on Pax3-bound loci. Using mass spectrometry and genomic studies, we identify the ubiquitously expressed LIM-domain binding protein 1 (Ldb1) as the mediator of looping interactions at a subset of Pax3 binding sites. Ldb1 is recruited to Pax3-bound elements independently of CTCF-Cohesin, and is necessary for efficient deposition of H3K4me1 at these sites and chromatin looping. When Ldb1 is deleted in Pax3-expressing cells in vivo, specification of migratory myogenic progenitors is severely impaired. These results highlight Ldb1 requirement for Pax3 myogenic activity and demonstrate how transcription factors can promote formation of sub-topologically associated domain interactions involved in lineage specification.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Line
  • Chromatin / metabolism
  • Chromosomes, Mammalian / chemistry
  • Chromosomes, Mammalian / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Embryo, Mammalian
  • Female
  • Fibroblasts
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental*
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Histones / metabolism
  • Humans
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Mouse Embryonic Stem Cells
  • Muscle Development*
  • PAX3 Transcription Factor / metabolism*

Substances

  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • LIM Domain Proteins
  • Ldb1 protein, mouse
  • PAX3 Transcription Factor
  • Pax3 protein, mouse