Chromatin dysfunction facilitates stem cells aging in atypical laminopathy-based progeria Mandibuloacral dysplasia type A (MAD)

Nuclear lamins orchestrate the nuclear envelope architecture to maintain nuclear homeostasis, such as nuclear integrity and chromatin organization. The LMNA mutations lead to a variety of laminopathies, including progeroid syndrome. Other than typical Hutchinson-Gilford progeria syndrome (HGPS), the mechanism of LMNA mutation associated atypical progeria remains largely unexplored. We used patient-specific induced pluripotent stem cells (iPSCs) and their derivatives to remodel an LMNA (c.1579 C>T, p.R527C) mutation that causes Mandibuloacral dysplasia type A (MAD). Vascular lineages, including vascular smooth muscle cells (VSMCs) and endothelial cells (VECs), exhibited premature ageing phenotypes, such as genome instability and nuclear deformations, whereas neural lineages showed no obvious defects. Based on the observation that MAD-iPSCs derived mesenchymal stem cells (MSCs) also recapitulated accelerated senescence, an integrated multi-omics approach was adapted to reveal the underlying mechanisms of stem cells ageing. We found that among available human MSCs ageing models, MAD-MSCs had the highest transcriptional similarity to normal ageing hMSCs. The nuclear lamina-chromatin interaction was dramatically altered for both A and B type lamin-associating domains (LADs) as well as non-LADs binding sites, resulting in ageing-associated gene dysregulations. Chromatin state analysis further showed increased chromatin accessibility, enhancer remodelling, global chromatin compartments loss, topologically associating domains (TADs) and TAD boundaries reorganization in MAD-MSCs. These hierarchical chromatin reorganizations, coupled with gene dysregulation as consequences, expedited the MAD-MSCs ageing. Collectively, this study revealed a multilevel chromatin dysregulation contributed to ageing significantly in a laminopathy-mediated atypical progeroid syndrome. High-throughput profiling of gene expression, Lamins binding, histone modifications, 3D chromatin organizations in iPSC-derived human mesenchymal stem cells (hMSCs) of MAD patient or normal person.