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Three distinct Atoh1 enhancers cooperate for sound receptor hair cell development [ATAC-seq]

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. Atoh1 expression is dynamic and tightly regulated during development, but the cis-regulatory elements mediating this regulation remain unresolved. Unexpectedly, we found that deleting the only recognized Atoh1 enhancer, defined here as Eh1, failed to impair HC development. By using ATAC-seq (assay for transposase-accessible chromatin with high-throughput sequencing), we discovered two additional Atoh1 enhancers: 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 effective Atoh1 regulation during HC development, indicating potential therapeutic approaches for HC regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE181310 | GEO | 2022/07/22

REPOSITORIES: GEO

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Three distinct Atoh1 enhancers cooperate for sound receptor hair cell development [CUT&RUN]

Project description: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. Atoh1 expression is dynamic and tightly regulated during development, but the cis-regulatory elements mediating this regulation remain unresolved. Unexpectedly, we found that deleting the only recognized Atoh1 enhancer, defined here as Eh1, failed to impair HC development. By using ATAC-seq (assay for transposase-accessible chromatin with high-throughput sequencing), we discovered two additional Atoh1 enhancers: 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 effective Atoh1 regulation during HC development, indicating potential therapeutic approaches for HC regeneration.

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Three distinct Atoh1 enhancers cooperate for sound receptor hair cell development

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Transcriptome-wide comparison of the impact of Atoh1 and miR-183 family on pluripotent stem cells and multipotent otic progenitors

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Project description:The functional unit of the inner ear consists of hair cells (HCs) and neurons in the inner ear. Both genes are induced early in development, but Atoh1 expression is counteracted by Neurog1. As a result, HC development is prevented during neurogenesis. This work aimed at understanding the molecular basis of this interaction. Atoh1 regulation depends on a 3’Atoh1-enhancer that is the site for Atoh1 autoregulation. This enhancer recapitulates Atoh1 expression in the embryo and contains putative binding sites for several transcription factors, including basic helix-loop-helix (bHLH) factors like Atoh1, Neurog1 and Hes/Hey repressors. Reporter assays on chick embryos and P19 cells show that Neurog1 hampers the autoactivation of Atoh1, the effect being cell autonomous and independent on Notch activity. ATAC-seq analysis shows that the region B of the 3’Atoh1-enhancer is accessible during development and sufficient for both activation and repression. Neurog1 requires the regions flanking the class A E-box bound by Atoh1 to show its repressor effect. However, Neurog1 does not require binding to DNA for Atoh1 repression and prevention of HC formation, but the dimerization domains Helix-1 and Helix-2. The repression of Atoh1 by Neurog1 does not involve the direct interaction between Atoh1 and Neurog1, but rather an indirect effect on the levels of Atoh1 protein. The results suggest that Neurog1 induces the acceleration of Atoh1 mRNA degradation and the consequent reduction of protein levels. Such a mechanism dissociates the prevention of Atoh1 expression in neuro-sensory progenitors from the unfolding of the neurogenic program.

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Characterization of the transcriptomes of Atoh1-induced hair cells in the mouse cochlea

Project description:Mammalian cochlea hair cells can be regenerated from the adjacent supporting cells in many ways, however, the newly hair cells are immature and without hearing function almost. The expression of Atoh1 is an important maker of the appearance of newly hair cells, many approaches of inner ear hair cells’ regeneration are concerned with the transcription factor Atoh1. However, most new HCs are immature HCs, and they do not have the function of mature HCs and eventually die a few weeks after regeneration. Thus promoting the maturation and survival of new HCs is the primary focus of HC regeneration field. We used RNA-Seq analysis to compare the differences between the transcriptomes of Atoh1 overexpression-induced new HCs and the original HCs, and to define the factors that might help to promote the maturation and survival of new HCs.

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Single cell gene expression profile of adult cochlear explants over the course of hair cell regeneration stimulated by Atoh1 activation [DoxVehicleAtoh1]

Project description:Strategies to overcome irreversible cochlear hair cell (HC) damage and loss are of vital importance to develop a treatment for hearing loss. HC regeneration in adult cochlea relies on a two-phase process: 1) Reprogramming mature cochlear (SCs) to regain the properties of their younger selves; 2) Activating Atoh1, a gene responsible for HC fate-determining, in the reprogrammed adult SCs for HC regeneration. We have shown that, by transient co-activation of Myc and NICD (Notch1 intracellular domain), the adult mouse cochlea can be successfully reprogrammed to a relatively younger stage and regain progenitor capacity, with the regeneration of HCs following Atoh1 overexpression in vitro and in vivo. To identify molecules to reprogram mature cochlear SCs and HC regeneration, we utilized single-cell RNA sequencing and uncovered the pathways and their target genes underlying MYC/NICD-mediated reprogramming. We used an in-house adult cochlea explant culture system and carried out single-cell RNA sequencing to examine the gene expression profiles of cochlear explants from a transgenic mouse model, rtTa/tet-Myc/-tet-NICD, in response to Dox-induced MYC/NICD co-activation. We compared gene expression profiles between Atoh1 activation vs. MYC/NICD/Atoh1 co-activation.

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A Cell Type-Specific Approach to Elucidate the Role of miR-96 in Inner Ear Hair Cells

Project description:Mutations in miRNA-96, a microRNA expressed within the hair cells (HCs) of the inner ear, result in progressive hearing loss in both mouse models and humans. While previous studies have delved into miR-96 transcriptional cascades via whole organ of Corti microarray experiments of diminuendo (Mir96Dmdo) mice, they face limitations in pinpointing cell type-specific differentially expressed genes. This hinders the ability to conclusively determine if the effects of Mir96Dmdo are specifically within HCs and contribute to the observed abnormal Mir96Dmdo HC phenotype and determine the role of miR-96 in HCs. In this study, we generate the first HC-specific RNA-sequencing (RNA-seq) datasets from Mir96Dmdo; Atoh1/nGFP+ postnatal day 1 wildtype, heterozygous, and homozygous mutant mice. Our differential gene expression analysis between Mir96Dmdo homozygous mutant HCs compared to wildtype HCs identified 215 upregulated and 428 downregulated genes. Many significantly downregulated genes in Mir96Dmdo homozygous mutant HCs have established roles in HC development and/or known roles in deafness such as Myo15, Myo7a, Ush1c Gfi1, and Ptprq, some of which were not previously identified in other miR-96 datasets. In addition, active modules of protein-protein interaction networks of significantly downregulated genes in Mir96Dmdo homozygous mutant HCs reveal enrichment in GO terms with biological functions such as sound perception and endocytosis. Genes significantly upregulated in Mir96Dmdo homozygous mutant HCs, which are more likely to be direct targets of miR-96, show higher expression in wildtype supporting cells compared to wildtype HCs, suggesting a role of miR-96 in suppressing non-HC genes during HC development. Finally, all generated HC-specific Mir96Dmdo RNA-seq datasets from this manuscript are now publicly available in the miR-96 specific gEAR profile (https://umgear.org/p?l=miR96).

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