Three distinctAtoh1enhancers cooperate for sound receptor hair cell development

Author:

Luo Zhengnan12ORCID,Du Yi23ORCID,Li Shuting12ORCID,Zhang He12,Shu Muya23,Zhang Di12ORCID,He Shunji1ORCID,Wang Guangqin12ORCID,Lu Falong23,Liu Zhiyong124ORCID

Affiliation:

1. State Key Laboratory of Neuroscience, Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China

2. University of Chinese Academy of Sciences, Beijing 100049, China

3. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China

4. Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201210, China

Abstract

Cochlear hair cells (HCs) in the inner ear are responsible for sound detection. For HC fate specification, the master transcription factor Atoh1 is both necessary and sufficient.Atoh1expression is dynamic and tightly regulated during development, but thecis-regulatory elements mediating this regulation remain unresolved. Unexpectedly, we found that deleting the only recognizedAtoh1enhancer, defined here as Eh1, failed to impair HC development. By using the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), we discovered two additionalAtoh1enhancers: Eh2 and Eh3. Notably, Eh2 deletion was sufficient for impairing HC development, and concurrent deletion of Eh1 and Eh2 or all three enhancers resulted in nearly complete absence of HCs. Lastly, we showed that Atoh1 binds to all three enhancers, consistent with its autoregulatory function. Our findings reveal that the cooperative action of three distinct enhancers underpins effectiveAtoh1regulation during HC development, indicating potential therapeutic approaches for HC regeneration.

Funder

Ministry of Science and Technology of the People's Republic of China

CAS | BFSE | Key Research Program of Frontier Science, Chinese Academy of Sciences

National Natural Science Foundation of China

STCSM | Science and Technology Innovation Plan Of Shanghai Science and Technology Commission

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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