美国麻省理工学院Li-Huei Tsai、Hiruy S. Meharena等研究人员合作发现，唐氏综合症引起的衰老破坏神经祖细胞的核结构。相关论文于2022年1月6日发表在《细胞—干细胞》杂志上。

研究人员表示，唐氏综合征（DS）是一种由21号染色体三倍体（T21）驱动的遗传性疾病，其特点是有广泛的神经发育和身体残疾。对DS患者组织样本的转录组分析显示，T21会诱发全基因组的转录破坏。然而，T21对核结构的影响及其与转录组的相互作用仍然未知。

研究人员发现与人类诱导多能干细胞（iPSC）不同，iPSC衍生的神经祖细胞（NPC）表现出全基因组的"染色体内翻"，薄层相关域的破坏，以及对T21反应的全局染色质可及性变化，与衰老细胞特有的转录和核结构变化一致。用抗衰老药物治疗T21缺失的NPC可以缓解与DS相关的转录、分子和细胞功能障碍。这些研究结果提供了T21和全局转录破坏之间的机制联系，并表明衰老相关的表型可能在DS的神经发育发病机制中发挥关键作用。

附：英文原文

Title: Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors

Author: Hiruy S. Meharena, Asaf Marco, Vishnu Dileep, Elana R. Lockshin, Grace Y. Akatsu, James Mullahoo, L. Ashley Watson, Tak Ko, Lindsey N. Guerin, Fatema Abdurrob, Shruthi Rengarajan, Malvina Papanastasiou, Jacob D. Jaffe, Li-Huei Tsai

Issue&Volume: 2022/01/06

Abstract: Down syndrome (DS) is a genetic disorder driven by the triplication of chromosome 21 (T21) and characterized by a wide range of neurodevelopmental and physical disabilities. Transcriptomic analysis of tissue samples from individuals with DS has revealed that T21 induces a genome-wide transcriptional disruption. However, the consequences of T21 on the nuclear architecture and its interplay with the transcriptome remain unknown. In this study, we find that unlike human induced pluripotent stem cells (iPSCs), iPSC-derived neural progenitor cells (NPCs) exhibit genome-wide “chromosomal introversion,” disruption of lamina-associated domains, and global chromatin accessibility changes in response to T21, consistent with the transcriptional and nuclear architecture changes characteristic of senescent cells. Treatment of T21-harboring NPCs with senolytic drugs alleviates the transcriptional, molecular, and cellular dysfunctions associated with DS. Our findings provide a mechanistic link between T21 and global transcriptional disruption and indicate that senescence-associated phenotypes may play a key role in the neurodevelopmental pathogenesis of DS.

DOI: 10.1016/j.stem.2021.12.002

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00486-0