Early chromatin conformational changes in Hutchinson-Gilford progeria syndrome revealed by heterochromatin analysis

Hutchinson-Gilford Progeria Syndrome (HGPS) is characterized by the progressive accumulation of progerin, an aberrant form of Lamin A, leading to chromatin structure disruption, in particular by interfering with Lamina Associated Domains. Although several cellular and molecular alterations have been characterized, it is still yet unclear how chromatin structure changes translate into premature senescence. Moreover, early events in chromatin remodeling could not be detected so far. We developed a new high-throughput sequencing-based method, for genome-wide characterization of heterochromatin accessibility changes. We named our technology SAMMY-seq (Sequential Analysis of MacroMolecules accessibilitY), as a tribute to Sammy Basso, the founder of the Italian Progeria Association. Using SAMMY-seq on early passage HGPS primary fibroblasts we were able to detect chromatin structure alterations, in terms of accessibility changes. Of note, these structural changes are not accompanied by H3K9me3 alterations but affect the regulation Polycomb regulated bivalent genes. Our findings reinforce previous studies showing that a correct chromatin architecture is necessary to cell fate determination and that alterations of PcG occur early in HGPS-derived cells.