Nuclear pore density controls heterochromatin reorganization during senescence

Abstract

During oncogene-induced senescence (OIS), heterochromatin is lost from the nuclear periphery and forms internal senescence-associated heterochromatin foci (SAHFs). We show that an increased nuclear pore density during OIS is responsible for SAHF formation. In particular, the nucleoporin TPR is necessary for both formation and maintenance of SAHFs. Loss of SAHFs does not affect cell cycle arrest but abrogates the senescence-associated secretory phenotype—a program of inflammatory cytokine gene activation. Our results uncover a previously unknown role of nuclear pores in heterochromatin reorganization in mammalian nuclei and demonstrate the importance of heterochromatin organization for a specific gene activation program.

Modulation of Cell Identity by Modification of Nuclear Pore Complexes

“…In animal cells, NPCs have been shown to modulate both chromatin organization and gene expression. As examples of the role of NPCs in chromatin organization, the nuclear basket protein Tpr is required for the exclusion of perinuclear heterochromatin from NPC-associated areas in HeLa cells infected with poliovirus (Krull et al, 2010), influences HIV integration sites by maintaining an open chromatin architecture near the NPC (Lelek et al, 2015;Wong et al, 2015), and promotes the formation and maintenance of senescence-associated heterochromatin foci in the nuclear interior in Ras-induced senescent cells (Boumendil et al, 2019). NPCs modulate gene expression by associating not only with gene promoters, but also with enhancers and super-enhancers to promote enhancer-promoter interactions through chromatin loops (Ibarra et al, 2016;Pascual-Garcia et al, 2017).…”

Nucleoporin 153 links nuclear pore complex to chromatin architecture by mediating CTCF and cohesin binding at cis-regulatory elements and TAD boundaries

“…In mammalian cells, NUP153 has been associated with establishment of heterochromatin domains in interphase cells 92 . Furthermore, NUP153 have been implicated compartmentalization in transcription factors at the NPC in response to activation of signal transduction pathways during cellular senescence, cell migration and cell proliferation 89,92,93,94 . Our results showing a functional cooperation between NUP153 and architectural proteins suggests that mammalian NUP153 may have a role in multistep organization and/or insulation of site-specific higher-order chromatin around the NPCs.…”

Proteomics Approaches to Define Senescence Heterogeneity and Chemotherapy Response

“…In parallel, the density of nuclear pore increases in senescent cells as a consequence of nucleoporins’ upregulation. As a consequence, the association of heterochromatin with the nuclear envelope is reduced and this further promotes the formation of intra‐nuclear SAHFs . Importantly, DNA damage and chromatin reorganizations induced the production of a specific secretome known as the senescence‐associated secretory phenotype (SASP).…”

“…As a consequence, the association of heterochromatin with the nuclear envelope is reduced and this further promotes the formation of intra-nuclear SAHFs. [9] Importantly, DNA damage and chromatin reorganizations induced the production of a specific secretome known as the senescenceassociated secretory phenotype (SASP). The presence of chromatin fragments in the cytoplasm activates the cGAS-STING pathway and the secretion of inflammatory cytokines in response to the NFkB and C/EBP transcription factors.…”