Biology subjects

Nadalin, F.

Publications and source records attributed to Nadalin, F..

3 recordsLinked to original sources

bioRxiv2023

Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution

Cancer is a highly heterogeneous disease, where phenotypically distinct subpopulations coexist and could be primed to different fates. Both genetic and epigenetic factors may drive cancer evolution, however little is known about whether and how such a process is pre-encoded in cancer clones. Using single-cell multi-omic lineage tracing and phenotypic assays, we investigate the predictive features of either tumour initiation or drug tolerance within the same cancer population. Clones primed to tumour initiation in vivo display two distinct transcriptional states at the baseline. Remarkably, these states share a distinctive DNA accessibility profile, highlighting an epigenetic basis for tumour initiation. The drug tolerant niche is also largely pre-encoded, but only partially overlaps the tumour-initiating one and evolves following two genetically and transcriptionally distinct trajectories. Our study highlights coexisting genetic, epigenetic and transcriptional determinants of cancer evolution, unravelling the molecular complexity of pre-encoded tumour phenotypes.

genomics↗

bioRxiv2022

Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages

Aging is characterized by gradual immune dysfunction and increased risk for many diseases, including respiratory infections. Genomic instability is thought to play a central role in the aging process but the mechanisms that damage nuclear DNA in aging are insufficiently defined. Cells that migrate or reside within confined environments experience forces applied to their nucleus, leading to transient nuclear envelope (NE) ruptures. NE ruptures are associated with DNA damage, and Lamin A/C is required to limit these events. Here, we show that Lamin A/C protects lung alveolar macrophages from NE rupture and hallmarks of aging. Lamin A/C ablation in immune cells results in a selective depletion of lung alveolar macrophages (AM) and a heightened susceptibility to influenza infection. Lamin A/C-deficient AM that persist display constitutive nuclear envelope rupture marks, DNA damage and p53-dependent senescence. In wild-type mice, we found that AM migrate within constricted spaces in vivo, at heights that induce NE rupture and DNA damage. AM from aged wild-type mice and from Lamin A/C-deficient mice share an upregulated lysosomal signature with CD63 expression, and we find that CD63 is required to clear damaged DNA in macrophages. We propose that induction of genomic instability by NE disruption represents a mechanism of aging in alveolar macrophages.

immunology↗

bioRxiv2022

Single-cell RNA-Seq analysis reveals dual sensing of HIV-1 in blood Axl+ dendritic cells

Sensing of incoming viruses represents one of the pivotal tasks of dendritic cells (DC). Human primary blood DC encompass various subsets that are diverse in their susceptibility and response to HIV-1. The recent identification of Axl+DC, a new blood DC subset, endowed with unique capacities to bind, replicate, and transmit HIV-1 prompted us to evaluate its anti-viral response. We show that HIV-1 induced two main broad and intense transcriptional programs in different Axl+DC potentially induced by different sensors; a NF-{kappa}B-mediated program that led to DC maturation and efficient antigen-specific CD4+T cell activation, and a program mediated by STAT1/2 that activated type I IFN and an ISG response. These responses were absent from cDC2 exposed to HIV-1 except when viral replication occurred. Finally, Axl+DC actively replicating HIV-1 identified by quantification of viral transcripts exhibited a mixed NF-{kappa}B/ISG innate response. Our results suggest that the route of HIV-1 entry may dictate different innate sensing pathway by DC.

immunology↗