Adult Stem Cell Research Center, Seoul National University, Republic of Korea.
Cell Mol Life Sci. 2011 Jan;68(2):325-36. doi: 10.1007/s00018-010-0457-9. Epub 2010 Jul 21.
Cellular senescence involves a reduction in adult stem cell self-renewal, and epigenetic regulation of gene expression is one of the main underlying mechanisms. Here, we observed that the cellular senescence of human umbilical cord blood-derived multipotent stem cells (hUCB-MSCs) caused by inhibition of histone deacetylase (HDAC) activity leads to down-regulation of high mobility group A2 (HMGA2) and, on the contrary, to up-regulation of p16(INK)⁴(A), p21(CIP)¹(/WAF)¹ and p27(KIP)¹. We found that let-7a1, let-7d, let-7f1, miR-23a, miR-26a and miR-30a were increased during replicative and HDAC inhibitor-mediated senescence of hUCB-MSCs by microRNA microarray and real-time quantitative PCR. Furthermore, the configurations of chromatins beading on these miRNAs were prone to transcriptional activation during HDAC inhibitor-mediated senescence. We confirmed that miR-23a, miR-26a and miR-30a inhibit HMGA2 to accelerate the progress of senescence. These findings suggest that HDACs may play important roles in cellular senescence by regulating the expression of miRNAs that target HMGA2 through histone modification.
细胞衰老涉及成体干细胞自我更新能力的降低，而基因表达的表观遗传调控是其主要的潜在机制之一。在这里，我们观察到组蛋白去乙酰化酶（HDAC）活性抑制导致人脐带血来源的多能干细胞（hUCB-MSCs）的细胞衰老，从而导致高迁移率族蛋白 A2（HMGA2）下调，而 p16(INK)⁴(A)、p21(CIP)¹(/WAF)¹和 p27(KIP)¹上调。我们发现，通过 microRNA 微阵列和实时定量 PCR，在 hUCB-MSCs 的复制和 HDAC 抑制剂介导的衰老过程中，let-7a1、let-7d、let-7f1、miR-23a、miR-26a 和 miR-30a 增加。此外，在 HDAC 抑制剂介导的衰老过程中，这些 miRNAs 上的染色质珠的构型易于转录激活。我们证实 miR-23a、miR-26a 和 miR-30a 通过抑制 HMGA2 来抑制 HMGA2，从而加速衰老的进程。这些发现表明，HDACs 可能通过组蛋白修饰调节靶向 HMGA2 的 miRNA 的表达，从而在细胞衰老中发挥重要作用。
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