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 an aberrant form of Lamin A, called progerin. Progerin leads to dysmorphic nuclei and chromatin structure disruption, in particular by interfering with Lamina Associated Domains. Several cellular and molecular alterations have been characterized, yet it is still 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, named SAMMY-seq, for genome-wide characterization of heterochromatin accessibility changes. SAMMY-seq allows identifying H3K9me3 reach regions associated to Lamina in normal cells. Using SAMMY-seq we were able to detect early stage changes of chromatin structure in primary fibroblasts of HGPS. These structural changes do not disrupt the distribution of H3K9me3 but are associated with transcriptional disregulation of Polycomb target genes. Our results show that SAMMY-seq is a sensitive and flexible technique to characterize heterochromatin alterations.