The Atoh7 remote enhancer provides transcriptional robustness during retinal ganglion cell development

Joel B. Miesfeld, Noor M. Ghiasvand, Brennan Marsh-Armstrong, Nicholas Marsh-Armstrong, Eric B. Miller, Pengfei Zhang, Suman K. Manna, Robert J. Zawadzki, Nadean L. Brown, Tom Glaser

Research output: Contribution to journalArticle

Abstract

The retinal ganglion cell (RGC) competence factor ATOH7 is dynamically expressed during retinal histogenesis. ATOH7 transcription is controlled by a promoter-adjacent primary enhancer and a remote shadow enhancer (SE). Deletion of the ATOH7 human SE causes nonsyndromic congenital retinal nonattachment (NCRNA) disease, characterized by optic nerve aplasia and total blindness. We used genome editing to model NCRNA in mice. Deletion of the murine SE reduces Atoh7 messenger RNA (mRNA) fivefold but does not recapitulate optic nerve loss; however, SEdel/knockout (KO) trans heterozygotes have thin optic nerves. By analyzing Atoh7 mRNA and protein levels, RGC development and survival, and chromatin landscape effects, we show that the SE ensures robust Atoh7 transcriptional output. Combining SE deletion and KO and wild-type alleles in a genotypic series, we determined the amount of Atoh7 needed to produce a normal complement of adult RGCs, and the secondary consequences of graded reductions in Atoh7 dosage. Together, these data reveal the workings of an evolutionary fail-safe, a duplicate enhancer mechanism that is hardwired in the machinery of vertebrate retinal ganglion cell genesis.

Original languageEnglish (US)
Pages (from-to)21690-21700
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number35
DOIs
StatePublished - Sep 1 2020

Keywords

  • Glaucoma
  • Human genetic disorders
  • Optic disc area
  • Optic nerve
  • Shadow enhancer

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'The Atoh7 remote enhancer provides transcriptional robustness during retinal ganglion cell development'. Together they form a unique fingerprint.

  • Cite this