4D Genome Rewiring during Oncogene-Induced and Replicative Senescence

Sati, Satish; Bonev, Boyan; Szabo, Quentin; Jost, Daniel; Bensadoun, Paul; Serra, François; Loubière, Vincent; Papadopoulos, Giorgio L.; Rivera-Mulia, Juan Carlos; Fritsch, Lauriane; Bouret, Pauline; Castillo, David; Gelpi, Josep L. L.; Orozco, Modesto; Vaillant, Cédric; Pellestor, Franck; Bantignies, Frédéric; Martí‐Renom, Marc A.; Gilbert, David M.; Lemaı̂tre, Jean-Marc; Cavalli, Giacomo

doi:10.1016/j.molcel.2020.03.007

Cited by 136 publications

(183 citation statements)

References 81 publications

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“…Imaging studies have reported decondensation at chromocenters after Dnmt1 KO in mouse embryonic fibroblasts (Casas-Delucchi et al, 2012) and an increase in DNase-I sensitivity of the inactive X chromosome after 5-azacytidine treatment of gerbil lung fibroblasts (Jablonka et al, 1985). More recently, loss of compartmentalisation was found in senescent fibroblasts with DNMT1 knockdown (Sati et al, 2020). In contrast, a prior study using the HCT116 DKO1 hypomethylation cell model did not find an increase in genome-wide open chromatin, suggesting no chromosomal de-condensation (Pandiyan et al, 2013).…”

Section: Discussionmentioning

confidence: 94%

DNA methylation is required to maintain DNA replication timing precision and 3D genome integrity

Smith

Luu

et al. 2020

Preprint

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DNA replication timing and three-dimensional (3D) genome organisation are associated with distinct epigenome patterns across large domains during differentiation and cancer progression. However, it is unclear if alternations in the epigenome, in particular cancer-associated DNA hypomethylation, can directly promote higher order genome architectural alterations. Here, we use Hi-C and single cell Repli-Seq, in the colorectal cancer DNMT1 and DNMT3B DNA methyltransferases double knockout model, to determine the impact of DNA hypomethylation on replication timing and 3D genome organisation. First, we find that the hypomethylated cells show a striking loss of replication timing precision with gain of intra-population replication timing heterogeneity and loss of 3D genome compartmentalisation. Second, hypomethylated regions that undergo a large change in replication timing also show loss of allelic replication timing, including at cancer-related genes. Finally, we observe the striking formation of ectopic H3K4me3-H3K9me3 domains across hypomethylated regions where late replication is maintained, which we propose serve to prevent aberrant transcription and loss of genome organisation after DNA demethylation. Together, our results highlight a previously underappreciated role for DNA methylation in the maintenance of 3D genome architecture.

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Section: Discussionmentioning

confidence: 94%

DNA methylation is required to maintain DNA replication timing precision and 3D genome integrity

Smith

Luu

et al. 2020

Preprint

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“…Whether these topological changes are related to changes in the levels of chromatin-bound CTCF or cohesin remains to be tested. Furthermore, a subset of genes activated upon OIS are located adjacent in the linear genome to regions that form SAHF and depend on SAHF formation to engage in TSS-TSS interactions that enhance their transcription (Sati et al, 2020), therefore heterochromatin repositioning during senescence causes upregulation of nearby genes by altering their interaction profiles.…”

Section: Senescence-associated Heterochromatin Focimentioning

confidence: 99%

Heterochromatin as an Important Driver of Genome Organization

Penagos-Puig

Furlan-Magaril

2020

Front. Cell Dev. Biol.

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Heterochromatin is a constituent of eukaryotic genomes with functions spanning from gene expression silencing to constraining DNA replication and repair. Inside the nucleus, heterochromatin segregates spatially from euchromatin and is localized preferentially toward the nuclear periphery and surrounding the nucleolus. Despite being an abundant nuclear compartment, little is known about how heterochromatin regulates and participates in the mechanisms driving genome organization. Here, we review pioneer and recent evidence that explores the functional role of heterochromatin in the formation of distinct chromatin compartments and how failure of the molecular mechanisms forming heterochromatin leads to disarray of genome conformation and disease.

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“…Pioneer transcription factors (that directly bind condensed chromatin) are critical in establishing new cell fate competence: they grant longterm chromatin access to non-pioneer factors and help determine cell identity by opening and licensing the enhancer landscape [68,70,71]. In addition, DNA methylation could play an important role in establishment of senescence as recently was shown for a DNMT1dependent downregulation of BRCA1/ZNF350/RBBP8 repressor complex in the course of oncogene-induced senescence [72]. Thus, efforts to identify different factors and the signaling pathways that they control could be critical in understanding the feasibility of rejuvenating senescent LSECs as a therapeutic strategy.…”

Section: Reprogramming Senescent Lsecsmentioning

confidence: 99%

LSEC model of aging

Grosse

Bulavin

2020

Aging

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The accumulation of senescent cells has been shown detrimental in many contexts [1-5]. In turn, the analysis of senescence in vascular endothelial cells is one of the main directions in the field of vascular aging as it plays a key role in the initiation, progression, and advancement of cardio-vascular diseases [3, 6-9]. While attenuating senescence has already been shown to ameliorate several pathological conditions, more recent work suggested that elimination of senescent cells could be advantageous for health and lifespan [4, 10-12]. Removing certain senescent cells that can be robustly replaced without conferring changes on organ structure or function is clearly beneficial. However, accumulating data suggest that there are functionally important senescent cell types that might not be efficiently replaced under physiological conditions, especially in old organisms. For example, age-induced senescence has been recently described in hypothalamic stem cells [13], while we found a significant build-up of senescence in liver sinusoid endothelial cells (LSECs). LSECs are fenestrated endothelial cells that line the hepatic sinusoids. These cells have several important physiological roles, including facilitating the bi-directional transfer of substrates between the blood and hepatocytes, endocytosing circulating proteins, regulating immunotolerance, and maintaining sinusoidal microenvironment [14-24]. LSECs are the main cell type responsible for clearing blood-borne macromolecular waste [14-16], including most viruses [17-19] and lipopolysaccharides (LPS) [20, 21]. Furthermore, LSECs are responsible for the selective uptake of high-density lipoprotein [20, 22], in this way governing cardiovascular risk and all-cause mortality [23, 24]. Among the many toxins that are removed by LSECs, oxidized low density lipoprotein (oxLDL) [25, 26] is of specific interest as a major atherogenic substance [27-29]. Other toxic agents endocytosed by LSECs include Advanced Glycation End products (AGEs)heterogenous metabolic byproducts formed by non-enzymatic irreversible protein glycosylation/glycoxidation and that are resistant to proteolysis [30-32]. The accumulation of AGEs in tissues is harmful, observed in several pathological conditions [33-35], and thought to result from chronic hyperglycemia and increased oxidative and carbonyl stress [36-38]. The removal of both oxLDL and AGEs, however, is an inefficient process and their build up, as seen in several pathological conditions or after a www.aging-us.com

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4D Genome Rewiring during Oncogene-Induced and Replicative Senescence

Cited by 136 publications

References 81 publications

DNA methylation is required to maintain DNA replication timing precision and 3D genome integrity

DNA methylation is required to maintain DNA replication timing precision and 3D genome integrity

Heterochromatin as an Important Driver of Genome Organization

LSEC model of aging

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