Cis-regulatory basis of sister cell type divergence in the vertebrate retina

Daniel P. Murphy, Andrew E.O. Hughes, Karen A. Lawrence, Connie A. Myers, Joseph C. Corbo

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Multicellular organisms evolved via repeated functional divergence of transcriptionally related sister cell types, but the mechanisms underlying sister cell type divergence are not well understood. Here, we study a canonical pair of sister cell types, retinal photoreceptors and bipolar cells, to identify the key cis-regulatory features that distinguish them. By comparing open chromatin maps and transcriptomic profiles, we found that while photoreceptor and bipolar cells have divergent transcriptomes, they share remarkably similar cis-regulatory grammars, marked by enrichment of K50 homeodomain binding sites. However, cell class-specific enhancers are distinguished by enrichment of E-box motifs in bipolar cells, and Q50 homeodomain motifs in photoreceptors. We show that converting K50 motifs to Q50 motifs represses reporter expression in bipolar cells, while photoreceptor expression is maintained. These findings suggest that partitioning of Q50 motifs within cell type-specific cis-regulatory elements was a critical step in the evolutionary divergence of the bipolar transcriptome from that of photoreceptors.

Original languageEnglish
Article numbere48216
JournaleLife
Volume8
DOIs
StatePublished - Oct 2019

Bibliographical note

Funding Information:
The authors would like to thank Leo Volkov and Yohey Ogawa for critical reading of the manuscript. The Otx2-GFP mouse line was a generous gift from Dr. Thomas Lamonerie (Université Côte d’Azur), and the Grm6-YFP line was a generous gift from Dr. Daniel Kerschensteiner (Washington University). We also credit the ENCODE consortium for the DNase-seq datasets, the Genome Technology Access Core (GTAC) in the Department of Genetics at Washington University in St. Louis for next-generation sequencing, and the Flow Cytometry Core in the Department of Pathology and Immunology at Washington University in Saint Louis for FACS services. This work was supported by the National Institute of Health (EY025196, EY026672, and EY024958 to JCC and T32EY013360 and F32EY029571 to DPM)

Funding Information:
The authors would like to thank Leo Volkov and Yohey Ogawa for critical reading of the manuscript. The Otx2-GFP mouse line was a generous gift from Dr. Thomas Lamonerie (Universit? C?te d?Azur), and the Grm6-YFP line was a generous gift from Dr. Daniel Kerschensteiner (Washington University). We also credit the ENCODE consortium for the DNase-seq datasets, the Genome Technology Access Core (GTAC) in the Department of Genetics at Washington University in St. Louis for next-generation sequencing, and the Flow Cytometry Core in the Department of Pathology and Immunology at Washington University in Saint Louis for FACS services. This work was supported by the National Institute of Health (EY025196, EY026672, and EY024958 to JCC and T32EY013360 and F32EY029571 to DPM).

Publisher Copyright:
© Murphy et al.

ASJC Scopus subject areas

  • Neuroscience (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Immunology and Microbiology (all)

Fingerprint

Dive into the research topics of 'Cis-regulatory basis of sister cell type divergence in the vertebrate retina'. Together they form a unique fingerprint.

Cite this