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

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.

miR-376a-3p and miR-376b-3p overexpression in Hutchinson-Gilford progeria fibroblasts inhibits cell proliferation and induces premature senescence

“…In HGPS cells, progerin accumulates with passages and induces chromatin conformational changes ( Harhouri et al., 2017 ; Köhler et al., 2020 ; Lionetti et al., 2020 ; Robin and Magdinier, 2016 ; Sebestyén et al., 2020 ; Shumaker et al., 2006 ). We hypothesized that the enrichment of overexpressed miRNAs from the same region could be secondary to chromatin remodeling in HGPS fibroblasts, as supported by other studies at different loci in other contexts ( McCord et al., 2013 ; Merkerova et al., 2018 ; Oldenburg et al., 2017 ; Wood et al., 2014 ).…”

Targeting SerpinE1 reverses cellular features of Hutchinson-Gilford progeria syndrome

“…Interestingly, analysis of available datasets indicates that SerpinE1 was not upregulated in other cell types, such as endothelial cells, vascular smooth muscle cells and aorta cells (Bersini et al 2020;von Kleeck et al 2021), suggesting a fibroblast-specific induction of SerpinE1 in HGPS patients. Indeed, analysis of publicly available datasets generated from HGPS fibroblasts revealed a loss of LMNA binding to SerpinE1 promoter (McCord et al 2013), with a consensual reduction in repressive chromatin marks (H3K27me3) at SerpinE1 promoter (Sebestyén et al 2020). These data suggest that SerpinE1 expression is induced as a direct consequence of typical loss of heterochromatin by alteration of nuclear lamina, rather than secondary events developed in cultured HGPS fibroblasts.…”

The needle and the haystack: single molecule tracking to probe the transcription factor search in eukaryotes

“…Functionally, the impact of the nuclear environment on the TF search could be addressed on systems where chromatin organization is deeply modulated, for example in rod cells of nocturnal animals, featuring heterochromatin inversion [ 89 ], during differentiation of pluripotent cells or in those disease models that display genome-wide perturbation of chromatin organization, such as progeria [ 90 ]. Combining SMT analysis of TF diffusion with high-throughput analysis of gene positioning in these models could help us understanding how target selectivity is achieved in living cells.…”