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


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 hard-wired in the machinery of vertebrate retinal ganglion cell genesis.

SUBMITTER: Miesfeld JB 

PROVIDER: S-EPMC7474671 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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The <i>Atoh7</i> remote enhancer provides transcriptional robustness during retinal ganglion cell development.

Miesfeld Joel B JB   Ghiasvand Noor M NM   Marsh-Armstrong Brennan B   Marsh-Armstrong Nicholas N   Miller Eric B EB   Zhang Pengfei P   Manna Suman K SK   Zawadzki Robert J RJ   Brown Nadean L NL   Glaser Tom T  

Proceedings of the National Academy of Sciences of the United States of America 20200817 35


The retinal ganglion cell (RGC) competence factor ATOH7 is dynamically expressed during retinal histogenesis. <i>ATOH7</i> transcription is controlled by a promoter-adjacent primary enhancer and a remote shadow enhancer (SE). Deletion of the <i>ATOH7</i> 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 <i>Atoh7</i> messenger RNA  ...[more]

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