Enhancer transcription identifies cis-regulatory elements for photoreceptor cell types

Development. 2020 Feb 5;147(3):dev184432. doi: 10.1242/dev.184432.

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.

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

Publication types

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

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • Female
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • RNA, Untranslated / genetics
  • RNA, Untranslated / metabolism
  • Regulatory Sequences, Nucleic Acid / genetics*
  • Retinal Cone Photoreceptor Cells / metabolism*
  • Retinal Rod Photoreceptor Cells / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription, Genetic / genetics*
  • Transcriptome

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Eye Proteins
  • Homeodomain Proteins
  • Nrl protein, mouse
  • RNA, Untranslated
  • Trans-Activators
  • cone rod homeobox protein