Laboratory of Stem Cells & Cell reprogramming, Department of Chemistry, Dongguk University, 100-715, Seoul, Korea.
Laboratory of Protein Engineering, Department of Biomedical Engineering, Dongguk University, 04620, Seoul, Korea.
Aging Cell. 2023 Jun;22(6):e13825. doi: 10.1111/acel.13825. Epub 2023 Mar 25.
Partial cellular reprogramming via transient expression of Oct4, Sox2, Klf4, and c-Myc induces rejuvenation and reduces aged-cell phenotypes. In this study, we found that transcriptional activation of the endogenous Oct4 gene by using the CRISPR/dCas9 activator system can efficiently ameliorate hallmarks of aging in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). We observed that the dCas9-Oct4 activator induced epigenetic remodeling, as evidenced by increased H3K9me3 and decreased H4K20me3 levels, without tumorization. Moreover, the progerin accumulation in HGPS aorta was significantly suppressed by the dCas9 activator-mediated Oct4 induction. Importantly, CRISPR/dCas9-activated Oct4 expression rescued the HGPS-associated vascular pathological features and lifespan shortening in the mouse model. These results suggest that partial rejuvenation via CRISPR/dCas9-mediated Oct4 activation can be used as a novel strategy in treating geriatric diseases.
通过瞬时表达 Oct4、Sox2、Klf4 和 c-Myc 进行部分细胞重编程可诱导衰老逆转并减少衰老细胞表型。在这项研究中，我们发现，使用 CRISPR/dCas9 激活系统对内源性 Oct4 基因进行转录激活，可以有效地改善亨廷顿病样 2 型早衰综合征（HGPS）小鼠模型的衰老标志物。我们观察到，dCas9-Oct4 激活剂诱导了表观遗传重塑，表现为 H3K9me3 水平增加和 H4K20me3 水平降低，但没有导致肿瘤化。此外，dCas9 激活剂介导的 Oct4 诱导显著抑制了 HGPS 主动脉中的 progerin 积累。重要的是，CRISPR/dCas9 激活的 Oct4 表达挽救了小鼠模型中与 HGPS 相关的血管病理特征和寿命缩短。这些结果表明，通过 CRISPR/dCas9 介导的 Oct4 激活进行部分重编程可以作为治疗老年病的一种新策略。
