Enhancer transcription identifies cis-regulatory elements for photoreceptor cell types

Carlos Perez-Cervantes, Linsin A. Smith, Rangarajan D. Nadadur, Andrew E.O. Hughes, Sui Wang, Joseph C. Corbo, Constance Cepko, Nicolas Lonfat, Ivan P. Moskowitz

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Identification of cell type-specific cis-regulatory elements (CREs) is crucial for understanding development and disease, although identification of functional regulatory elements remains challenging. We hypothesized that context-specific CREs could be identified by context-specific non-coding RNA (ncRNA) profiling, based on the observation that active CREs produce ncRNAs. We applied ncRNA profiling to identify rod and cone photoreceptor CREs from wild-type and mutant mouse retinas, defined by presence or absence, respectively, of the rod-specific transcription factor (TF) Nrl. Nrl-dependent ncRNA expression strongly correlated with epigenetic profiles of rod and cone photoreceptors, identified thousands of candidate rod- and cone-specific CREs, and identified motifs for rod- and cone-specific TFs. Colocalization of NRL and the retinal TF CRX correlated with rod-specific ncRNA expression, whereas CRX alone favored cone-specific ncRNA expression, providing quantitative evidence that heterotypic TF interactions distinguish cell type-specific CRE activity. We validated the activity of novel Nrl-dependent ncRNA-defined CREs in developing cones. This work supports differential ncRNA profiling as a platform for the identification of cell type-specific CREs and the discovery of molecular mechanisms underlying TF-dependent CRE activity.

Original languageEnglish
Article numberdev184432
JournalDevelopment (Cambridge)
Volume147
Issue number3
DOIs
StatePublished - 2020

Keywords

  • Cis-regulatory element
  • Cone
  • Crx
  • Enhancer
  • Gene regulatory network
  • Non-coding RNA (ncRNA)
  • Nrl
  • Photoreceptor
  • Rod
  • Transcription factor

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