Journal
DEVELOPMENT
Volume 147, Issue 3, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.184432
Keywords
Enhancer; Transcription factor; Non-coding RNA (ncRNA); Photoreceptor; Nrl; Crx; Rod; Cone; Gene regulatory network; Cis-regulatory element
Categories
Funding
- National Institutes of Health (NIH) [R01HL126509, R01HL148719, R01HL147571, R33 HL123857, R01EY024958, R01EY025196, R01EY026672, F30 HL131298, R01EY029771]
- American Heart Association Collaborative Sciences Award [AHA17CSA33610126]
- Howard Hughes Medical Institute
- Fondation Leducq
- NIH
- Biological Sciences Division of the University of Chicago
- Swiss National Science Foundation (Schweizerischer Nationalfonds zur Forderung derWissenschaftlichen Forschung)
- Human Frontier Science Program
- American Diabetes Association Pathway Program [1-16-INI16]
- NIH from National Heart, Lung, and Blood Institute [5T32GM007197-43, T32HL007381]
- Argonne National Laboratory [1S10OD018495-01]
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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) Nil. AM-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 Nri-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.
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