Biology subjects

Crabbe, L.

Publications and source records attributed to Crabbe, L..

3 recordsLinked to original sources

bioRxiv2026

Differential Enhancer Activity and FOXF1 Levels Contribute to Higher Inflammatory Gene Expression of Fetal/Neonatal Versus Adult Fibroblasts in IR-induced Senescence

Some key inflammatory genes controlled by the RELA transcription factor are thought to be highly expressed in fibroblasts induced into senescence by ionizing radiation (IR) as part of the Senescent-Associated Secretory Phenotype (SASP). However, this view is based largely on studies of a limited number of fibroblast cell lines derived from fetal lung or neonatal foreskin. Here, we show that more than half of the primary adult fibroblast strains examined exhibit only weak induction of RELA-dependent inflammatory genes following IR-induced senescence. We define these fibroblasts as "low-responding" to distinguish them from fibroblasts that express high levels of inflammatory gene expression in response to IR. RNA-seq analysis indicated particularly weak IL1A and IL1B expression in low-responding fibroblasts. IL1-alpha and IL1-beta participate in a positive amplification loop for inflammatory gene expression in senescence. Addition of recombinant IL1-alpha or IL1-beta to these fibroblasts sufficed to induce high expression of inflammatory genes. Low-responding fibroblasts thus exhibit cell-autonomous defects in IL1A and IL1B gene activation in response to IR that explains their overall low expression of RELA-targeted inflammatory genes. This defect was correlated with reduced chromatin accessibility and H3-K27-acetylation at 2 putative enhancers in the intergenic region separating IL1A and IL1B, and deletion of either of these enhancers inhibited inflammatory gene expression in IR-induced senescence. Fibroblasts express distinct transcriptomes and we found that differential expression of the FOXF1 transcription factor gene in high-responding WI38 fetal lung fibroblasts contributes to inflammatory gene expression after IR. Our observations indicate that fibroblasts can be distinguished by their ability to manifest cell-autonomous induction of inflammatory genes under conditions of IR-induced senescence.

Cell Biology↗

bioRxiv2022

Spatial modeling of telomere intra-nuclear distribution reveals non-random organization that varies during cell cycle and depends on LAP2 and BAF

Genome organization within the 3D nuclear volume influences major biological processes but is completely lost during mitosis, which represents a major challenge to maintain cellular identity and cell fate. To restore a functional G1 nucleus for the next cell cycle, it is imperative to reestablish genome organization during post-mitotic nuclear assembly. Importantly, the configuration of linear chromosomes has been shown to directly impact spatial genome architecture. Both centromeres and telomeres are known to associate with nuclear structures, such as the nuclear envelope, and support chromatin distribution. Here, using high-resolution 3D imaging combined with 3D spatial statistics and modeling, we showed that telomeres generally followed a regular distribution compared to what is expected under a random organization. While the preferential localization of telomeres at nuclear periphery was restricted to early G1, we found a strong clustering of centromeres in addition to their predominant peripheral localization at all cell cycle stages. We then conducted a targeted screen using MadID to identify the molecular pathways driving or maintaining telomere anchoring to the nuclear envelope. Among these factors, we could show that LAP2 transiently localizes to telomeres in anaphase, at a stage where LAP2 initiates the reformation of the nuclear envelope. Moreover, co-depletion of LAP proteins and their partner BAF impacted telomere redistribution in the next interphase. There results suggest that in addition to their crucial role in genome protection, telomeres also participate in reshaping functional G1 nuclei after mitosis.

cell biology↗

bioRxiv2018

Replication stress induces mitotic death through parallel pathways regulated by WAPL and telomere deprotection

Mitotic catastrophe is a broad descriptor encompassing unclear mechanisms of cell death. Here we investigate replication stress-driven mitotic catastrophe in human cells and identify that replication stress principally induces mitotic death signalled through two independent pathways. In p53-compromised cells we find that lethal replication stress confers WAPL-dependent centromere cohesion defects that maintain spindle assembly checkpoint-dependent mitotic arrest in the same cell cycle. Mitotic arrest then drives cohesion fatigue and triggers mitotic death through a primary pathway of BAX/BAK-dependent apoptosis. Simultaneously, a secondary mitotic death pathway is engaged through non-canonical telomere deprotection, regulated by TRF2, Aurora B and ATM. Additionally, we find that suppressing mitotic death promotes genome instability in replication stressed cells through diverse mechanisms depending upon how cell death is averted. These data demonstrate how replication stress-induced mitotic catastrophe signals cell death with implications for cancer treatment and genome instability.

molecular biology↗