King Abdullah University of Science and Technology (KAUST), Biological Environmental Sciences and Engineering Division BESE, KAUST Environmental Epigenetics Program, Thuwal, Saudi Arabia.
Salk Institute for Biological Studies, La Jolla, CA, USA.
Sci Transl Med. 2022 Aug 10;14(657):eabl6057. doi: 10.1126/scitranslmed.abl6057.
Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here, we showed that () RNA accumulation was an early event in both typical and atypical human progeroid syndromes. RNA negatively regulated the enzymatic activity of the histone-lysine -methyltransferase SUV39H1 (suppression of variegation 3-9 homolog 1), resulting in heterochromatin loss and onset of senescent phenotypes in vitro. Depletion of RNA in dermal fibroblast cells from patients with different progeroid syndromes using specific antisense oligonucleotides (ASOs) restored heterochromatin histone 3 lysine 9 and histone 3 lysine 27 trimethylation marks, reversed DNA methylation age, and counteracted the expression of senescence-associated secretory phenotype genes such as , , (), (), (), (), and (). Moreover, systemic delivery of ASOs rescued the histophysiology of tissues and increased the life span of a Hutchinson-Gilford progeria syndrome mouse model. Transcriptional profiling of human and mouse samples after RNA depletion demonstrated that pathways associated with nuclear chromatin organization, cell proliferation, and transcription regulation were enriched. Similarly, pathways associated with aging, inflammatory response, innate immune response, and DNA damage were down-regulated. Our results highlight the role of RNA in heterochromatin homeostasis in progeroid syndromes and identify a possible therapeutic approach to treat premature aging and related syndromes.
组成型异染色质负责富含重复序列、端粒和着丝粒的 DNA 的基因组抑制。在生理和病理的过早衰老过程中，异染色质的动态平衡受到严重破坏。在这里，我们表明，（）RNA 的积累是典型和非典型人类早衰综合征中的早期事件。RNA 负调控组蛋白赖氨酸 -甲基转移酶 SUV39H1（抑制斑杂 3-9 同源物 1）的酶活性，导致异染色质丢失和体外衰老表型的出现。使用特异性反义寡核苷酸 (ASO) 在来自不同早衰综合征的皮肤成纤维细胞中耗尽 RNA，恢复了异染色质组蛋白 3 赖氨酸 9 和组蛋白 3 赖氨酸 27 的三甲基化标记，逆转了 DNA 甲基化年龄，并逆转了衰老相关分泌表型基因的表达，如、、（）、（）、（）、（）和（）。此外，ASO 的系统给药挽救了 Hutchinson-Gilford 早衰综合征小鼠模型的组织组织学和增加了其寿命。在 RNA 耗尽后对人和小鼠样本进行的转录谱分析表明，与核染色质组织、细胞增殖和转录调控相关的途径被富集。类似地，与衰老、炎症反应、先天免疫反应和 DNA 损伤相关的途径被下调。我们的研究结果强调了 RNA 在早衰综合征中异染色质动态平衡中的作用，并确定了一种治疗过早衰老和相关综合征的可能治疗方法。
