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Early Polycomb-target deregulations in Hutchinson-Gilford Progeria Syndrome revealed by heterochromatin analysis

By Endre Sebestyen, Fabrizia Marullo, Federica Lucini, Andrea Bianchi, Cristiano Petrini, Sara Valsoni, Ilaria Olivieri, Laura Antonelli, Francesco Gregoretti, Gennaro Oliva, Francesco Ferrari, Chiara Lanzuolo

Posted 10 Oct 2019
bioRxiv DOI: 10.1101/799668

Hutchinson-Gilford progeria syndrome (HGPS) is characterized by the progressive accumulation of progerin, an aberrant form of Lamin A. This leads to chromatin structure disruption, in particular by interfering with Lamina Associated Domains. Although several cellular and molecular alterations have been characterized, it is still unclear how chromatin structural changes translate into premature senescence in HGPS. Moreover, early events in chromatin remodeling have not been detected so far. We developed a new high-throughput sequencing-based method, named SAMMY-seq, for genome-wide characterization of heterochromatin accessibility changes. Using SAMMY-seq, we detected early stage alterations of chromatin structure in HGPS primary fibroblasts. Of note, these structural changes do not disrupt the distribution of H3K9me3 but are associated with site-specific H3K27me3 variations and transcriptional dysregulation of Polycomb target genes. Our results show that SAMMY-seq represents a novel and sensitive tool to characterize heterochromatin alterations. Moreover, we found that the assembly of lamin associated domains is strictly connected to the correct Polycomb repression, rapidly lost in early HGPS pathogenesis.

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