Epigenetic mechanisms underlying the failure of hair cell regeneration in mammals

哺乳动物毛细胞再生失败的表观遗传机制

• 批准号: 10440356
• 负责人: ANDREW P. MCMAHON
• 金额: $ 58.16万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440356
• 关键词: ATAC-seq; Acetylation; Adult; Birth; Cell Death; Cell Differentiation process; Cell Nucleus; Cells; ChIP-seq; Chromatin; Chromatin Structure; Cochlea; Complex; Data; Deacetylation; Dependence; Developmental Gene; Embryo; Epigenetic Process; Excision; Failure; Future; Gene Activation; Gene Silencing; Genes; Genetic Transcription; Goals; Hair Cells; Heterochromatin; Histone H3; Individual; Inner Supporting Cell; Labyrinth; Lateral; Lysine; Mammals; Mediating; Methods; Modeling; Modification; Molecular; Mus; Natural regeneration; Newborn Infant; Nucleosomes; Organ of Corti; Perinatal; Pharmacology; Physical condensation; Polycomb; Population; Regenerative Medicine; Regenerative capacity; Role; Sensory Hair; Structure; Supporting Cell; Techniques; Technology; Testing; Up-Regulation; Work; age related; deaf; disability; epigenetic silencing; epigenome; gene network; genome-wide; hair cell regeneration; hearing impairment; hearing restoration; inhibitor; knockout gene; notch protein; perinatal period; permanent hearing loss; postnatal; programs; regeneration potential; transcription factor; transcriptome; transcriptome sequencing; transdifferentiation

Project Summary/Abstract: Sensory hair cell regeneration does not occur spontaneously in the mature mammalian organ of Corti, making hearing loss permanent. The goal of this proposal is to identify the causes and mechanisms behind the failure of hair cell regeneration, as well as ways to stimulate regeneration in surviving populations of inner ear supporting cells in deafened individuals. Our primary hypothesis is that regeneration requires the re- engagement of developmental gene networks to guide supporting cells to a hair cell fate, and that during postnatal inner ear maturation, epigenetic barriers arise that block the re-activation of these gene networks. The goal is to develop methods to overcome these epigenetic barriers, and to establish new cell fates with regenerative potential within the organ of Corti. Experimentally, perinatal mice retain a latent capacity for direct supporting cell transdifferentiation to a hair cell-like fate, but this capacity is rapidly lost in the first weeks after birth. This age-dependent change in regenerative potential provides a window through which to investigate the transition from a permissive to a non-permissive state for this form of regeneration in the normally maturing organ of Corti. The work of this proposal is to elucidate the mechanism(s) of epigenetic control of transdifferentiation in perinatal supporting cells (Aim1) and to identify the machinery of maturation-related changes in epigenetic/chromatin structure in supporting cells of the inner ear. (Aim 2). We hypothesize that these changes are responsible for the failure of regeneration. Finally, to investigate the epigenetic structure of adult supporting cell chromatin in normal and deafened mice (Aim 3). We hypothesize that manipulation of the epigenetic state is an important approach for future regenerative medicine approaches to restoring lost hair cells.

项目概要/摘要： 在成熟的哺乳动物Corti器官中，感觉毛细胞再生不会自发发生， 永久性听力损失。本提案的目的是查明造成这一现象的原因和机制， 毛细胞再生的失败，以及刺激内耳存活群体再生的方法 支持细胞的能力。我们的主要假设是再生需要重新- 参与发育基因网络，以指导支持细胞的毛细胞的命运， 出生后内耳成熟，表观遗传障碍出现，阻碍这些基因网络的重新激活。 目标是开发克服这些表观遗传障碍的方法，并建立新的细胞命运， Corti器官的再生潜力。 在实验中，围产期小鼠保留了直接支持细胞转分化为 毛细胞一样的命运，但这种能力是迅速失去出生后的第一个星期。这种年龄依赖性的变化 再生潜力提供了一个窗口，通过它来研究从允许到不允许的过渡。 在正常成熟的Corti器官中，这种形式的再生处于非允许状态。开展工作 建议阐明转分化的表观遗传控制机制， 细胞（Aim 1），并确定在表观遗传/染色质结构的成熟相关的变化机制， 内耳的支持细胞。(Aim 2）。我们假设，这些变化是失败的原因。 再生最后，为了研究正常人和正常人成体支持细胞染色质的表观遗传结构， 免疫小鼠（Aim 3）。我们假设操纵表观遗传状态是一种重要的方法， 未来的再生医学方法来恢复失去的毛细胞。

项目成果

Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues.

小分子对LATS激酶的抑制可能会促进有丝分裂后哺乳动物组织中YAP依赖性的增殖。

• DOI: 10.1038/s41467-021-23395-3
• 发表时间: 2021-05-25
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Kastan N;Gnedeva K;Alisch T;Petelski AA;Huggins DJ;Chiaravalli J;Aharanov A;Shakked A;Tzahor E;Nagiel A;Segil N;Hudspeth AJ
• 通讯作者: Hudspeth AJ

GFI1 regulates hair cell differentiation by acting as an off-DNA transcriptional co-activator of ATOH1, and a DNA-binding repressor.

• DOI: 10.1038/s41598-022-11931-0
• 发表时间: 2022-05-12
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Jen HI;Singh S;Tao L;Maunsell HR;Segil N;Groves AK
• 通讯作者: Groves AK