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

Autor:	Shi T; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles CA 90033.; Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033., Kim Y; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles CA 90033.; Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033., Llamas J; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles CA 90033.; Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033., Wang X; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles CA 90033.; Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033., Fabian P; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles CA 90033., Lozito TP; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles CA 90033., Segil N; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles CA 90033.; Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033., Gnedeva K; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles CA 90033.; Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033., Crump JG; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles CA 90033.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Dec 17; Vol. 121 (51), pp. e2418098121. Date of Electronic Publication: 2024 Dec 13.
DOI:	10.1073/pnas.2418098121
Abstrakt:	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 plasticity in regenerative vertebrates. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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