Cis-regulatory elements (CREs) coordinate the output of transcriptional networks during development. Identifying CREs is thus a prime concern, but can be challenging as many of their features are shared with non-functional elements in the genome. Here, Nicolas Lonfat, Ivan Moskowitz and colleagues have taken advantage of the non-coding RNA (ncRNA) signature of functional enhancers to identify CREs in mouse photoreceptors. The study compared ncRNA abundance in wild-type versus Nrl mutant retinas, where cones, rather than rods, form the majority of photoreceptors. Deep sequencing revealed thousands of Nrl-activated (rod-expressed) and Nrl-repressed (cone-expressed) ncRNAs, the expression of which strongly correlated with that of nearby Nrl-dependent genes, and with the epigenetic profiles of rod and cone photoreceptors, respectively. Coincident co-binding of the retinal transcription factors (TFs) NRL and CRX was associated with Nrl-activated ncRNAs, whereas CRX binding alone was associated with Nrl-repressed ncRNAs. This analysis, associating TF binding patterns with relative ncRNA abundance (as a proxy for relative enhancer function), provided quantitative support for a heterotypic TF model of retinal cell type-specific gene regulation. Finally, the authors showed that Nrl-regulated ncRNAs efficiently predict functional CREs in photoreceptors in vivo. This study identified thousands of candidate CREs involved in rod and cone specification, and demonstrates the utility of ncRNA profiling for CRE discovery and analysis.
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February 2020
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