Chen Yilin, Bravo Juan I, Son Jyung Mean, Lee Changhan, Benayoun Bérénice A
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
Master of Science in Nutrition, Healthspan, and Longevity, University of Southern California, Los Angeles, CA 90089, USA.
Transl Med Aging. 2020;4:22-31. doi: 10.1016/j.tma.2019.12.003. Epub 2020 Jan 3.
In multi-cellular organisms, the control of gene expression is key not only for development, but also for adult cellular homeostasis, and deregulation of gene expression correlates with aging. A key layer in the study of gene regulation mechanisms lies at the level of chromatin: cellular chromatin states (. the 'epigenome') can tune transcriptional profiles, and, in line with the prevalence of transcriptional alterations with aging, accumulating evidence suggests that the chromatin landscape is altered with aging across cell types and species. However, although alterations in the chromatin make-up of cells are considered to be a hallmark of aging, little is known of the genomic loci that are specifically affected by age-related chromatin state remodeling and of their biological significance. Here, we report the analysis of genome-wide profiles of core histone H3 occupancy in aging male mouse tissues (. heart, liver, cerebellum and olfactory bulb) and primary cultures of neural stem cells. We find that, although no drastic changes in H3 levels are observed, local changes in H3 occupancy occur with aging across tissues and cells with both regions of increased or decreased occupancy. These changes are compatible with a general increase in chromatin accessibility at pro-inflammatory genes and may thus mechanistically underlie known shift in gene expression programs during aging.
在多细胞生物中，基因表达的调控不仅对发育至关重要，而且对成年细胞的内环境稳定也很关键，基因表达失调与衰老相关。基因调控机制研究的一个关键层面在于染色质水平：细胞染色质状态（即“表观基因组”）可以调节转录谱，而且，鉴于转录改变在衰老过程中普遍存在，越来越多的证据表明，染色质格局会随着衰老在不同细胞类型和物种中发生改变。然而，尽管细胞染色质组成的改变被认为是衰老的一个标志，但对于受年龄相关染色质状态重塑特异性影响的基因组位点及其生物学意义却知之甚少。在此，我们报告了对衰老雄性小鼠组织（心脏、肝脏、小脑和嗅球）以及神经干细胞原代培养物中核心组蛋白H3占有率的全基因组分析。我们发现，尽管未观察到H3水平有剧烈变化，但随着衰老，跨组织和细胞的H3占有率会发生局部变化，占有率有增加或减少的区域。这些变化与促炎基因处染色质可及性的普遍增加相一致，因此可能在机制上构成衰老过程中已知基因表达程序转变的基础。
