Biology subjects

Grossi, E.

Publications and source records attributed to Grossi, E..

3 recordsLinked to original sources

bioRxiv2024

The SWI/SNF PBAF complex facilitates REST occupancy at repressive chromatin

Multimeric SWI/SNF chromatin remodelers assemble into discrete conformations with unique complex functionalities difficult to dissect. Distinct cancers harbor mutations in specific subunits, altering the chromatin landscape, such as the PBAF-specific component ARID2 in melanoma. Here, we performed comprehensive epigenomic profiling of SWI/SNF complexes and their associated chromatin states in melanoma and melanocytes and uncovered a subset of PBAF-exclusive regions that coexist with PRC2 and repressive chromatin. Time-resolved approaches revealed that PBAF regions are generally less sensitive to ATPase-mediated remodeling than BAF sites. Moreover, PBAF/PRC2-bound loci are enriched for REST, a transcription factor that represses neuronal genes. In turn, absence of ARID2 and consequent PBAF complex disruption hinders the ability of REST to bind and inactivate its targets, leading to upregulation of synaptic transcripts. Remarkably, this gene signature is conserved in melanoma patients with ARID2 mutations. In sum, we demonstrate a unique role for PBAF in generating accessibility for a silencing transcription factor at repressed chromatin, with important implications for disease.

molecular biology↗

bioRxiv2024

Intervertebral disc cells from human back pain subjects exhibit TNFR1-mediated senescence and lack TNFR2-modulated repair capacity

Poor intervertebral disc (IVD) healing causes IVD degeneration (IVDD) and progression to herniation and back pain. This study identified distinct roles of TNF-receptors (TNFRs) in contributing to poor healing in painful IVDD. We first isolated IVDD tissue of back pain subjects and determined the complex pro-inflammatory mixture contained many chemokines for recruiting inflammatory cells. Single-cell RNA-sequencing of human IVDD tissues revealed these pro- inflammatory cytokines were dominantly expressed by a small macrophage-population. Human annulus fibrosus (hAF) cells treated with IVDD-conditioned media (CM) underwent senescence with greatly reduced metabolic rates and limited inflammatory responses. TNFR1 inhibition partially restored hAF cell metabolism sufficiently to enable a robust chemokine and cytokine response to CM. We showed that the pro-reparative TNFR2 was very limited on hIVD cell membranes so that TNFR2 inhibition with blocking antibodies or activation using Atsttrin had no effect on hAF cells with CM challenge. However, TNFR2 was expressed in high levels on macrophages identified in scRNA-seq analyses, suggesting their role in repair responses. Results therefore point to therapeutic strategies for painful IVDD involving immunomodulation of TNFR1 signaling in IVD cells to enhance metabolism and enable a more robust inflammatory response including recruitment or delivery of TNFR2 expressing immune cells to enhance IVD repair. SUMMARY STATEMENTTNFR1 signaling drives cells towards senesce and muted inflammatory response in painful intervertebral disc degeneration, while limited TNFR2 signaling may limit disc cell repair responses.

bioengineering↗

bioRxiv2024

A senescence-specific lncRNA controls metabolic rewiring of senescent cells

Despite the classical view of senescence as passive growth arrest, senescent cells remain metabolically active to be able to cope with the energetic demand of the senescence program. However, the mechanisms underlying this metabolic reprogramming remain poorly understood. We have identified sin-lncRNA, a previously uncharacterized lncRNA, that plays a pivotal role in this response. Sin-lncRNA is only expressed by senescent cells, induced by the senescence master regulator C/EBP{beta}. While strongly activated in senescence, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with the TCA enzyme dihydrolipoamide S-succinyltransferase (DLST) it facilitates its localization to the mitochondria. On the other hand, sin-lncRNA depletion results in DLST nuclear translocation linked to DLST-dependent transcriptional alteration of OXPHOS genes. While in highly proliferative cancer cells, sin-lncRNA expression remains undetected, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells results in deficient oxygen consumption and increased extracellular acidification, sensitizing the cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in cellular senescence to maintain metabolic homeostasis. Our findings reveal a new regulatory mechanism in which a lncRNA contributes to the adaptive metabolic changes in senescent cells, unveiling the existence of an RNA-dependent metabolic rewiring specific to senescent cells.

cell biology↗