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

Jen, Hsin-I; Hill, Matthew C.; Tao, Litao; Sheng, Kuanwei; Cao, Wenjian; Zhang, Hongyuan; Yu, Haoze V; Llamas, Juan; Zong, Chenghang; Martin, James F.; Segil, Neil; Groves, Andrew K.

doi:10.7554/elife.44328

Cited by 48 publications

(33 citation statements)

References 103 publications

(180 reference statements)

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“…It is possible that a small subset population of neonatal glial cells respond much better to ectopic Ngn1 and Neurod1 and are reprogrammed to SGN state with Mafb and Gata3 expression. The second is that reprogramming process itself is a stochastic process and there are various barriers at different steps, as also suggested by a recent Atoh1‐mediated reprogramming of adult mouse utricle SCs into HCs . We currently do not understand the mechanisms underlying the conversion of glial cells into SGN fate mediated by Ngn1 and Neurod1, nor how Ngn1 and Neurod1 regulate cell fate specification and differentiation in wild‐type SGNs.…”

Section: Discussionmentioning

confidence: 98%

“…The second is that reprogramming process itself is a stochastic process and there are various barriers at different steps, as also suggested by a recent Atoh1-mediated reprogramming of adult mouse utricle SCs into HCs. 43 We currently do not understand the mechanisms underlying the conversion of glial cells into SGN fate mediated by Ngn1 and Neurod1, nor how Ngn1 and Neurod1 regulate cell fate specification and differentiation in wild-type SGNs. Recently, it was reported that Ngn1 regulates CDK2 to promote proliferation in otic progenitors.…”

Section: Multiple Factors Contribute To the Heterogeneities Of New mentioning

confidence: 99%

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In vivo ectopic Ngn1 and Neurod1 convert neonatal cochlear glial cells into spiral ganglion neurons

Sun

et al. 2020

FASEB j.

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Damage or degeneration of inner ear spiral ganglion neurons (SGNs) causes hearing impairment. Previous in vitro studies indicate that cochlear glial cells can be reprogrammed into SGNs, however, it remains unknown whether this can occur in vivo. Here, we show that neonatal glial cells can be converted, in vivo, into SGNs (defined as new SGNs) by simultaneous induction of Neurog1 (Ngn1) and Neurod1. New SGNs express SGN markers, Tuj1, Map2, Prox1, Mafb and Gata3, and reduce glial cell marker Sox10 and Scn7a. The heterogeneity within new SGNs is illustrated by immunostaining and transcriptomic assays. Transcriptomes analysis indicates that well reprogrammed SGNs are similar to type I SGNs. In addition, reprogramming efficiency is positively correlated with the dosage of Ngn1 and Neurod1, but declined with aging. Taken together, our in vivo data demonstrates the plasticity of cochlear neonatal glial cells and the capacity of Ngn1 and Neurod1 to reprogram glial cells into SGNs. Looking ahead, we expect that combination of Neurog1 and Neurod1 along with other factors will further boost the percentage of fully converted (Mafb+/Gata3+) new SGNs.

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Section: Discussionmentioning

confidence: 98%

Section: Multiple Factors Contribute To the Heterogeneities Of New mentioning

confidence: 99%

In vivo ectopic Ngn1 and Neurod1 convert neonatal cochlear glial cells into spiral ganglion neurons

Sun

et al. 2020

FASEB j.

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“…However, ATAC-seq offers many benefits over comparable assays including a lower input material requirement, shorter assay time, in situ library preparation, and further protocol adaptation to fresh-frozen tissue [11]. These advantages have permitted precise in vivo regulatory genomic assays on small populations of sorted cells [12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

ATAC-seq normalization method can significantly affect differential accessibility analysis and interpretation

Reske

Wilson

Chandler

2020

Epigenetics & Chromatin

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Background: Chromatin dysregulation is associated with developmental disorders and cancer. Numerous methods for measuring genome-wide chromatin accessibility have been developed in the genomic era to interrogate the function of chromatin regulators. A recent technique which has gained widespread use due to speed and low input requirements with native chromatin is the Assay for Transposase-Accessible Chromatin, or ATAC-seq. Biologists have since used this method to compare chromatin accessibility between two cellular conditions. However, approaches for calculating differential accessibility can yield conflicting results, and little emphasis is placed on choice of normalization method during differential ATAC-seq analysis, especially when global chromatin alterations might be expected. Results: Using an in vivo ATAC-seq data set generated in our recent report, we observed differences in chromatin accessibility patterns depending on the data normalization method used to calculate differential accessibility. This observation was further verified on published ATAC-seq data from yeast. We propose a generalized workflow for differential accessibility analysis using ATAC-seq data. We further show this workflow identifies sites of differential chromatin accessibility that correlate with gene expression and is sensitive to differential analysis using negative controls. Conclusions: We argue that researchers should systematically compare multiple normalization methods before continuing with differential accessibility analysis. ATAC-seq users should be aware of the interpretations of potential bias within experimental data and the assumptions of the normalization method implemented.

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“…Viewed in this context, Notch signaling may act in a manner analogous to a construction scaffold-it specifies hair cell and supporting cell fates during development, but is not required to maintain these fates in the adult and is therefore dismantled by downregulation. This could be explained by changes in the epigenetic state of hair cell and supporting cell genes as the organ of Corti matures [104]. This raises the question of whether modifying the chromatin structure to be more accessible at hair cell gene loci and then modifying Notch signaling activity in the mature cochlea may lead to hair cell regeneration.…”

Section: A Future For Notch? Notch Signaling In the Inner Ear After Smentioning

confidence: 99%

Hear, Hear for Notch: Control of Cell Fates in the Inner Ear by Notch Signaling

Brown

Groves

2020

Biomolecules

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The vertebrate inner ear is responsible for detecting sound, gravity, and head motion. These mechanical forces are detected by mechanosensitive hair cells, arranged in a series of sensory patches in the vestibular and cochlear regions of the ear. Hair cells form synapses with neurons of the VIIIth cranial ganglion, which convey sound and balance information to the brain. They are surrounded by supporting cells, which nourish and protect the hair cells, and which can serve as a source of stem cells to regenerate hair cells after damage in non-mammalian vertebrates. The Notch signaling pathway plays many roles in the development of the inner ear, from the earliest formation of future inner ear ectoderm on the side of the embryonic head, to regulating the production of supporting cells, hair cells, and the neurons that innervate them. Notch signaling is re-deployed in non-mammalian vertebrates during hair cell regeneration, and attempts have been made to manipulate the Notch pathway to promote hair cell regeneration in mammals. In this review, we summarize the different modes of Notch signaling in inner ear development and regeneration, and describe how they interact with other signaling pathways to orchestrate the fine-grained cellular patterns of the ear.

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

Cited by 48 publications

References 103 publications

In vivo ectopic Ngn1 and Neurod1 convert neonatal cochlear glial cells into spiral ganglion neurons

In vivo ectopic Ngn1 and Neurod1 convert neonatal cochlear glial cells into spiral ganglion neurons

ATAC-seq normalization method can significantly affect differential accessibility analysis and interpretation

Hear, Hear for Notch: Control of Cell Fates in the Inner Ear by Notch Signaling

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