Role of co-repressor genomic landscapes in shaping the Notch response

PLoS Genet. 2017 Nov 20;13(11):e1007096. doi: 10.1371/journal.pgen.1007096. eCollection 2017 Nov.

Abstract

Repressors are frequently deployed to limit the transcriptional response to signalling pathways. For example, several co-repressors interact directly with the DNA-binding protein CSL and are proposed to keep target genes silenced in the absence of Notch activity. However, the scope of their contributions remains unclear. To investigate co-repressor activity in the context of this well defined signalling pathway, we have analysed the genome-wide binding profile of the best-characterized CSL co-repressor in Drosophila, Hairless, and of a second CSL interacting repressor, SMRTER. As predicted there was significant overlap between Hairless and its CSL DNA-binding partner, both in Kc cells and in wing discs, where they were predominantly found in chromatin with active enhancer marks. However, while the Hairless complex was widely present at some Notch regulated enhancers in the wing disc, no binding was detected at others, indicating that it is not essential for silencing per se. Further analysis of target enhancers confirmed differential requirements for Hairless. SMRTER binding significantly overlapped with Hairless, rather than complementing it, and many enhancers were apparently co-bound by both factors. Our analysis indicates that the actions of Hairless and SMRTER gate enhancers to Notch activity and to Ecdysone signalling respectively, to ensure that the appropriate levels and timing of target gene expression are achieved.

MeSH terms

  • Animals
  • Binding Sites
  • Co-Repressor Proteins / genetics
  • Co-Repressor Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Ecdysone / metabolism
  • Gene Expression Regulation, Developmental / genetics
  • Genomics
  • Protein Binding
  • Receptors, Notch / genetics*
  • Receptors, Notch / metabolism*
  • Regulatory Sequences, Nucleic Acid / genetics
  • Repressor Proteins / genetics
  • Signal Transduction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Co-Repressor Proteins
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Receptors, Notch
  • Repressor Proteins
  • Smr protein, Drosophila
  • Transcription Factors
  • H protein, Drosophila
  • Ecdysone