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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]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE218325 | GEO | 2023/06/01

REPOSITORIES: GEO

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Reprogramming of cochlear supporting cells by MYC/NICD co-activation.

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, 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 have shown that a 4-day treatment by Dox in cultured adult rtTa/tetMyc/-tet-NICD cochleae was sufficient to reprogram adult SCs for HC regeneration.

2022-06-03 | GSE205187 | GEO

Single cell gene expression profile of adult cochlear explants over the course of hair cell regeneration stimulated by chemical reprogramming [CocktailVehicleAtoh1]

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. We identified a combination (the cocktail) of drug-like molecules composing of small molecules and siRNAs to activate the pathways of Myc, Notch1, Wnt and cAMP. 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 chemical-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, in response to chemical-induced reprogramming. We compared gene expression profiles between Vehicle/ad.Atoh1 activation vs. Cocktail (chemical reprogramming)/ad.Atoh1 activation.

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Identification of intermediate transcriptome states and synergistic effects of Isl1 in Atoh1-mediated cochlear hair cell conversion

Project description:Ectopic expression of Atoh1 in non-sensory supporting cells (SCs) in mouse cochleae induces their conversion to hair cells (HCs) in vivo. cHCs in multiple intermediate states of the conversion process that most closely resembled neonatal differentiating HCs, but differed from the progenitors. We further identified 52 transcription factors that are differentially expressed in cHCs, SCs, and mature HCs and confirmed that Isl1 synergistically enhanced the efficiency of Atoh1-mediated HC conversion in cochlear explants. Our results demonstrate that direct HC conversion from SCs in vivo follows a different path from normal development and requires multiple factors for maximum efficiency and completion.

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Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Project description:Mammalian cochlear outer hair cells (OHCs) are essential for hearing. Severe hearing impairment follows OHC degeneration. Previous attempts at regenerating new OHCs from cochlear supporting cells (SCs) have been unsuccessful, notably lacking expression of the key OHC motor protein, Prestin. Thus, regeneration of Prestin+ OHCs represented a barrier to restoring auditory function in vivo. Here, we reported the successful in vivo conversion of adult mouse cochlear SCs into Prestin+ OHC-like cells through the concurrent induction of two key transcriptional factors known to be necessary for OHC development: Atoh1 and Ikzf2. Single cell RNA sequencing reveals the upregulation of 729 OHC genes and downregulation of 331 SC genes in OHC-like cells. The resulting differentiation status of these OHC-like cells was much more advanced than previously achieved. This study thus established an efficient approach to induce the regeneration of Prestin+ OHCs, paving the way for in vivo cochlear repair via SC transdifferentiation.

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

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.

2022-07-22 | GSE181310 | GEO

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

2022-07-22 | GSE181307 | GEO

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.

2019-04-10 | GSE129533 | GEO

Project description:Single-cell gene expression profile of adult cochlear explants over the course of hair cell regeneration stimulated by Atoh1 activation vs. MYC/NICD/Atoh1 co-activation

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Transcriptomic and epigenetic regulation of hair cell regeneration in the mouse utricle and its potentiation by Atoh1

Project description:The mammalian cochlea loses its ability to regenerate new hair cells prior to the onset of hearing. In contrast, the adult vestibular system can produce new hair cells in response to damage, or by reprogramming of supporting cells with the hair cell transcription factor Atoh1. We used RNA-seq and ATAC-seq to probe the transcriptional and epigenetic responses of utricle supporting cells to damage and Atoh1 transduction. We show that the improved regenerative response of the utricle correlates with a more accessible chromatin structure in utricle supporting cells compared to their cochlear counterparts. We also provide evidence that Atoh1 transduction of supporting cells is able to promote increased transcriptional accessibility of some hair cell genes. Our study offers a possible explanation for regenerative differences between sensory organs of the inner ear, but shows that additional factors to Atoh1 may be required for optimal reprogramming of hair cell fate.

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Unraveling the Molecular Landscape of Lead-Induced Cochlear Synaptopathy: A Quantitative Proteomic Analysis

Project description:This study investigates how lead exposure triggers cochlear synaptopathy and hearing loss in mice. Young-adult CBA/J mice were given lead acetate in drinking water for 28 days. We assessed hearing thresholds, outer hair cell activity, and synaptic changes in the cochlea. Lead exposure raises hearing thresholds, indicating cochlear synaptopathy. Notably affects synapses in the basal turn without impacting outer hair cells. In addition to this, lead altered the abundance of 352 synaptic proteins, with the synaptic vesicle cycle pathway prominently affected. Lead-induced cochlear synaptopathy targets basal cochlear regions, implicating synaptic vesicle cycle signaling in hearing loss. Revealing specific mechanisms behind lead-induced hearing deficits enhances targeted interventions and preventive strategies, advancing our understanding of lead induced hearing loss.

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