A new high-throughput sequencing-based technology reveals early deregulation of bivalent genes in Hutchinson-Gilford Progeria Syndrome

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

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Received Date: 11th November 19

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 some 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, demonstrating that SAMMY-seq represents a novel and sensitive tool to characterize heterochromatin remodeling. These structural changes do not disrupt the distribution of H3K9me3 suggesting that chromatin rearrangements precede H3K9me3 alterations observed at later passages. On the other hand, we found that in HGPS, changes in chromatin accessibility are associated with site-specific H3K27me3 variations and transcriptional dysregulation of Polycomb bivalent genes. Thus the correct assembly of lamin associated domains is functionally connected to the Polycomb repression, rapidly lost in early HGPS pathogenesis.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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