衰老小鼠耳蜗的染色质可及性和转录组图谱，以及与年龄相关的听力损失中潜在功能超级增强子的鉴定。

BACKGROUND: Presbycusis, also referred to as age-related hearing loss (ARHL), is a condition that results from the cumulative effects of aging on an individual's auditory capabilities. Given the limited understanding of epigenetic mechanisms in ARHL, our research focuses on alterations in chromatin-accessible regions. METHODS: We employed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) in conjunction with unique identifier (UID) mRNA-seq between young and aging cochleae, and conducted integrated analysis as well as motif/TF-gene prediction. Additionally, the essential role of super-enhancers (SEs) in the development of ARHL was identified by comparative analysis to previous research. Meanwhile, an ARHL mouse model and an aging mimic hair cell (HC) model were established with a comprehensive identification of senescence phenotypes to access the role of SEs in ARHL progression. RESULTS: The control cochlear tissue exhibited greater chromatin accessibility than cochlear tissue affected by ARHL. Furthermore, the levels of histone 3 lysine 27 acetylation were significantly depressed in both aging cochlea and aging mimic HEI-OC1 cells, highlighting the essential role of SEs in the development of ARHL. The potential senescence-associated super-enhancers (SASEs) of ARHL were identified, most of which exhibited decreased chromatin accessibility. The majority of genes related to the SASEs showed obvious decreases in mRNA expression level in aging HCs and was noticeably altered following treatment with JQ1 (a commonly used SE inhibitor). CONCLUSION: The chromatin accessibility in control cochlear tissue was higher than that in cochlear tissue affected by ARHL. Potential SEs involved in ARHL were identified, which might provide a basis for future therapeutics targeting SASEs related to ARHL.

背景：老年性聋，又称与年龄相关的听力损失（ARHL），是一种由个体听觉能力随年龄增长而累积效应引起的疾病。鉴于对 ARHL 中表观遗传机制的了解有限，我们的研究集中在染色质可及区域的改变上。

方法：我们在年轻和衰老耳蜗之间使用了转座酶可及染色质的高通量测序（ATAC-seq）与独特标识符（UID）mRNA-seq 的联合分析，并进行了综合分析以及基序/TF-基因预测。此外，通过与之前的研究进行比较分析，确定了超级增强子（SEs）在 ARHL 发展中的重要作用。同时，通过建立 ARHL 小鼠模型和衰老模拟毛细胞（HC）模型，全面鉴定衰老表型，研究 SEs 在 ARHL 进展中的作用。

结果：对照耳蜗组织的染色质可及性高于受 ARHL 影响的耳蜗组织。此外，在衰老耳蜗和衰老模拟 HEI-OC1 细胞中，组蛋白 3 赖氨酸 27 乙酰化水平均显著降低，这突出了 SEs 在 ARHL 发展中的重要作用。确定了 ARHL 的潜在衰老相关超级增强子（SASEs），其中大多数的染色质可及性降低。与 SASEs 相关的大多数基因在衰老 HCs 中的 mRNA 表达水平明显降低，并且在用 JQ1（一种常用的 SE 抑制剂）处理后明显改变。

结论：对照耳蜗组织的染色质可及性高于受 ARHL 影响的耳蜗组织。确定了与 ARHL 相关的潜在 SEs，这可能为未来针对与 ARHL 相关的 SASEs 的治疗提供依据。