Dynamic binding of RBPJ is determined by notch signaling status

David Castel, Philippos Mourikis, Stefanie J.J. Bartels, Arie B. Brinkman, Shahragim Tajbakhsh, Hendrik G. Stunnenberg

Research output: Contribution to journalArticlepeer-review

188 Citations (Scopus)

Abstract

Notch signaling plays crucial roles in mediating cell fate choices in all metazoans largely by specifying the transcriptional output of one cell in response to a neighboring cell. The DNA-binding protein RBPJ is the principle effector of this pathway in mammals and, together with the transcription factor moiety of Notch (NICD), regulates the expression of target genes. The prevalent view presumes that RBPJ statically occupies consensus binding sites while exchanging repressors for activators in response to NICD. We present the first specific RBPJ chromatin immunoprecipitation and high-throughput sequencing study in mammalian cells. To dissect the mode of transcriptional regulation by RBPJ and identify its direct targets, whole-genome binding profiles were generated for RBPJ; its coactivator, p300; NICD; and the histone H3 modifications H3 Lys 4 trimethylation (H3K4me3), H3 Lys 4 monomethylation (H3K4me1), and histone H3 Lys 27 acetylation (H3K27ac) in myogenic cells under active or inhibitory Notch signaling conditions. Our results demonstrate dynamic binding of RBPJ in response to Notch activation at essentially all sites co-occupied by NICD. Additionally, we identify a distinct set of sites where RBPJ recruits neither NICD nor p300 and binds DNA statically, irrespective of Notch activity. These findings significantly modify our views on how RBPJ and Notch signaling mediate their activities and consequently impact on cell fate decisions.

Original languageEnglish
Pages (from-to)1059-1071
Number of pages13
JournalGenes and Development
Volume27
Issue number9
DOIs
Publication statusPublished - 1 May 2013
Externally publishedYes

Keywords

  • ChIP-seq
  • NICD
  • Notch
  • P300
  • Rbpj
  • RNA-seq
  • Skeletal muscle

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