IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy.
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Nat Commun. 2020 Dec 8;11(1):6274. doi: 10.1038/s41467-020-20048-9.
Hutchinson-Gilford progeria syndrome is a genetic disease caused by an aberrant form of Lamin A resulting in chromatin structure disruption, in particular by interfering with lamina associated domains. Early molecular alterations involved in chromatin remodeling have not been identified thus far. Here, we present SAMMY-seq, a high-throughput sequencing-based method for genome-wide characterization of heterochromatin dynamics. Using SAMMY-seq, we detect early stage alterations of heterochromatin structure in progeria primary fibroblasts. These structural changes do not disrupt the distribution of H3K9me3 in early passage cells, thus suggesting that chromatin rearrangements precede H3K9me3 alterations described at later passages. On the other hand, we observe an interplay between changes in chromatin accessibility and Polycomb regulation, with site-specific H3K27me3 variations and transcriptional dysregulation of bivalent genes. We conclude that the correct assembly of lamina associated domains is functionally connected to the Polycomb repression and rapidly lost in early molecular events of progeria pathogenesis.
亨廷顿氏舞蹈症-早老综合征是一种由异常形式的 lamin A 引起的遗传疾病，导致染色质结构紊乱，特别是通过干扰核纤层相关结构域。迄今为止，尚未确定涉及染色质重塑的早期分子改变。在这里，我们提出了 SAMMY-seq，一种基于高通量测序的全基因组异染色质动力学特征分析方法。使用 SAMMY-seq，我们检测到早发性早衰原代成纤维细胞中异染色质结构的早期改变。这些结构变化不会破坏早期细胞中 H3K9me3 的分布，因此表明染色质重排先于在较晚传代中描述的 H3K9me3 改变。另一方面，我们观察到染色质可及性和 Polycomb 调控之间的相互作用，具有特定位点的 H3K27me3 变化和双价基因的转录失调。我们得出结论，核纤层相关结构域的正确组装与 Polycomb 抑制功能相关，并在早衰发病的早期分子事件中迅速丢失。
