我们使用出生后耳蜗的类器官探索​​了染色质可及性和转录程序的变化，以从有丝分裂后支持细胞分化耳蜗毛细胞。这些类器官含有具有分化前庭毛细胞和耳蜗毛细胞转录特征的细胞。轨迹的构建将 Lgr5 细胞识别为毛细胞的祖细胞，基因组数据揭示了导致毛细胞的基因调控网络。我们验证了这些网络，证明了类器官分化过程中转录因子（TF）的表达和预测结合位点的动态变化。我们确定了毛细胞发育的已知调节因子 Atoh1、Pou4f3 和 Gfi1，分析预测了调节因子 Tcf4（Atoh1 的 E 蛋白和异二聚化伙伴）和 Ddit3（CCAAT/增强子结合蛋白 (C/EBP)）抑制 Hes1 并激活 Wnt 信号相关基因的转录。破译哺乳动物耳蜗支持细胞的毛细胞再生信号揭示了毛细胞 (HC) 再生的候选者，这种再生在成人中是有限的。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

We explore the changes in chromatin accessibility and transcriptional programs for cochlear hair cell differentiation from postmitotic supporting cells using organoids from postnatal cochlea. The organoids contain cells with transcriptional signatures of differentiating vestibular and cochlear hair cells. Construction of trajectories identifies Lgr5+ cells as progenitors for hair cells, and the genomic data reveal gene regulatory networks leading to hair cells. We validate these networks, demonstrating dynamic changes both in expression and predicted binding sites of transcription factors (TFs) during organoid differentiation. We identify known regulators of hair cell development, Atoh1, Pou4f3, and Gfi1, and the analysis predicts the regulatory factors Tcf4, an E-protein and heterodimerization partner of Atoh1, and Ddit3, a CCAAT/enhancer-binding protein (C/EBP) that represses Hes1 and activates transcription of Wnt-signaling-related genes. Deciphering the signals for hair cell regeneration from mammalian cochlear supporting cells reveals candidates for hair cell (HC) regeneration, which is limited in the adult.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.