SAMMY-seq reveals early alteration of heterochromatin and deregulation of bivalent genes in Hutchinson-Gilford Progeria Syndrome

Endre Sebestyén, Fabrizia Marullo, Federica Lucini, Cristiano Petrini, Andrea Bianchi, Sara Valsoni, Ilaria Olivieri, Laura Antonelli, Francesco Gregoretti, Gennaro Oliva, Francesco Ferrari () and Chiara Lanzuolo ()
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Endre Sebestyén: IFOM, The FIRC Institute of Molecular Oncology
Fabrizia Marullo: Institute of Cell Biology and Neurobiology, National Research Council
Federica Lucini: Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”
Cristiano Petrini: IFOM, The FIRC Institute of Molecular Oncology
Andrea Bianchi: Institute of Cell Biology and Neurobiology, National Research Council
Sara Valsoni: IRCCS Santa Lucia Foundation
Ilaria Olivieri: Institute of Cell Biology and Neurobiology, National Research Council
Laura Antonelli: Institute for High Performance Computing and Networking, National Research Council
Francesco Gregoretti: Institute for High Performance Computing and Networking, National Research Council
Gennaro Oliva: Institute for High Performance Computing and Networking, National Research Council
Francesco Ferrari: IFOM, The FIRC Institute of Molecular Oncology
Chiara Lanzuolo: Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-20048-9

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