Long-range Atoh1 enhancers maintain competency for hair cell regeneration in the inner ear

• 成果类型: Article
• 署名作者: Shi, Tuo; Kim, Yeeun; Llamas, Juan; Wang, Xizi; Fabian, Peter; Lozito, Thomas P.; Segil, Neil; Gnedeva, Ksenia; Crump, J. Gage
• 署名单位: University of Southern California; University of Southern California
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13631
• DOI: 10.1073/pnas.2418098121
• 发表日期: 2024-12-17
• 关键词: atoh1 expression; supporting cells; gene-expression; lateral-line; organ; fate; notch; proliferation; cochlea; math1

摘要

During tissue regeneration, lineage- related cells can switch their fate to replace missing cells. This cell plasticity is particularly prominent in more regenerative vertebrates such as zebrafish, yet the molecular basis by which cells transdifferentiate into another cell type upon injury remains unclear. Here, we investigate the epigenetic basis of regenerative transdifferentiation in the inner ear, where supporting cells (SCs) generate mechanosensory hair cells (HCs) upon damage. By comparing the chromatin landscapes in regenerative zebrafish and green anole lizards versus nonregenerative mice, we identified a class of enhancers that function in progenitors to generate HCs and then are selectively maintained in SCs of regenerative vertebrates to regenerate HCs. In particular, we uncovered a syntenic class of long- range enhancers for Atoh1, a master transcription factor for HC differentiation. In the absence of injury, these enhancers maintain accessibility in SCs through adulthood but are prevented from driving zebrafish atoh1a expression through Notch repression. Deletion of these enhancers not only impaired atoh1a expression and HC formation during development but also blocked the ability of SCs to transdifferentiate into HCs during regeneration. Moreover, defects were specific to the inner ear versus the lateral line, revealing distinct mechanisms of regeneration in these mechanosensory organs. These findings reveal a class of regenerative enhancer that maintains competency of inner ear SCs to upregulate atoh1a and transdifferentiate into HCs upon damage. We propose that the continued accessibility of developmental enhancers for one cell fate in lineage- related cells may be a common theme underlying adult cell in vertebrates.