背景:长老会,也称为年龄相关听力损失(ARHL),是衰老对个体听觉能力的累积影响导致的一种状况。鉴于对ARHL表观遗传机制的理解有限,我们的研究重点是染色质可接近区域的改变.
方法:我们采用了转座酶可接近染色质的高通量测序(ATAC-seq)和独特标识符(UID)mRNA-seq结合年轻和衰老耳蜗,并进行了整合分析以及基序/TF基因预测。此外,通过与以往研究的比较分析,确定了超增强剂(SEs)在ARHL发展中的重要作用.同时,建立了ARHL小鼠模型和衰老模拟毛细胞(HC)模型,并对衰老表型进行了全面鉴定,以了解SEs在ARHL进展中的作用。
结果:对照耳蜗组织表现出比ARHL影响的耳蜗组织更大的染色质可及性。此外,组蛋白3赖氨酸27乙酰化水平在老化的耳蜗和老化模拟HEI-OC1细胞中均显著降低,强调SEs在ARHL发展中的重要作用。鉴定出ARHL潜在的衰老相关超级增强子(SASEs),其中大多数表现出染色质可及性降低。与SASE相关的大多数基因在老化的HC中显示出mRNA表达水平的明显下降,并且在用JQ1(一种常用的SE抑制剂)处理后显著改变。
结论:受ARHL影响的对照组耳蜗组织的染色质可及性高于耳蜗组织。确定了参与ARHL的潜在SE,这可能为未来针对ARHL相关SASEs的治疗提供基础。
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).
CONCLUSIONS: 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.