Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
Neurology and Neurorehabilitation Units, IRCCS San Raffaele Hospital, Milan, Italy.
Nat Commun. 2024 Jul 30;15(1):6419. doi: 10.1038/s41467-024-50794-z.
Multiple Sclerosis (MS) is a heterogeneous inflammatory and neurodegenerative disease with an unpredictable course towards progressive disability. Treating progressive MS is challenging due to limited insights into the underlying mechanisms. We examined the molecular changes associated with primary progressive MS (PPMS) using a cross-tissue (blood and post-mortem brain) and multilayered data (genetic, epigenetic, transcriptomic) from independent cohorts. In PPMS, we found hypermethylation of the 1q21.1 locus, controlled by PPMS-specific genetic variations and influencing the expression of proximal genes (CHD1L, PRKAB2) in the brain. Evidence from reporter assay and CRISPR/dCas9 experiments supports a causal link between methylation and expression and correlation network analysis further implicates these genes in PPMS brain processes. Knock-down of CHD1L in human iPSC-derived neurons and knock-out of chd1l in zebrafish led to developmental and functional deficits of neurons. Thus, several lines of evidence suggest a distinct genetic-epigenetic-transcriptional interplay in the 1q21.1 locus potentially contributing to PPMS pathogenesis.
多发性硬化症（MS）是一种异质性炎症和神经退行性疾病，其致残进程不可预测。由于对潜在机制的了解有限，治疗进行性 MS 具有挑战性。我们使用来自独立队列的跨组织（血液和死后大脑）和多层数据（遗传、表观遗传、转录组学）研究了与原发性进展型多发性硬化症（PPMS）相关的分子变化。在 PPMS 中，我们发现了 1q21.1 基因座的过度甲基化，该基因座受 PPMS 特异性遗传变异控制，并影响大脑中近端基因（CHD1L、PRKAB2）的表达。来自报告基因检测和 CRISPR/dCas9 实验的证据支持甲基化和表达之间的因果关系，相关性网络分析进一步表明这些基因与 PPMS 大脑过程有关。在人类 iPSC 衍生神经元中敲低 CHD1L 和在斑马鱼中敲除 chd1l 导致神经元发育和功能缺陷。因此，有几项证据表明 1q21.1 基因座存在独特的遗传-表观遗传-转录相互作用，可能导致 PPMS 发病机制。
