Biology subjects

Shanks, A.

Publications and source records attributed to Shanks, A..

3 recordsLinked to original sources

bioRxiv2025

Evening blue light exposure during adolescence induces avoidance behaviors and rewires medial amygdala circuit.

Adolescents are being increasingly exposed to artificial blue light from electronic devices, raising concerns about its effects on brain development and mental health. The medial amygdala (MeA), a brain region critical for emotional regulation, is light-sensitive, yet how evening blue light during puberty influences its circuitry and behavior remains unknown. Using a light cycle disruption paradigm, we found that adolescent mice exposed to evening blue light displayed increased avoidance behaviors compared to those exposed to darkness or reduced blue light conditions. Single-nuclei RNA sequencing revealed altered cell-type composition and disrupted synaptic communication pathways in the MeA. In vivo calcium imaging showed increased activity in MeA somatostatin neurons during avoidance behaviors, while chemogenetic inhibition of these neurons reduced these behaviors. Our findings identify the MeA as a key integrator of emotional responses to environmental blue light, suggesting evening blue light exposure during puberty as a potential risk factor for affective disorders. TeaserEvening blue light exposure during adolescence alters medial amygdala functions, leading to anxiety-like behaviors.

neuroscience↗

bioRxiv2023

Genome-wide CRISPR screen identifies KEAP1 as a genetic dependency of ARID1A in an ovarian clear cell carcinoma model

ARID1A is the core DNA binding subunit of the BAF chromatin remodeling complex and is mutated in about [~]8% of all cancers. The frequency of ARID1A loss varies between cancer subtypes, with clear cell ovarian carcinoma (CCOC) presenting the highest incidence at >50% of cases. Despite a growing understanding of the consequences of ARID1A-loss in cancer, there remains limited targeted therapeutic options for ARID1A-deficient cancers. Using a genome-wide CRISPR screening approach, we identify KEAP1 as a genetic dependency of ARID1A in CCOC. Depletion or chemical perturbation of KEAP1 results in selective growth inhibition of ARID1A-KO cell lines and edited primary endometrial epithelial cells. While we confirm that KEAP1-NRF2 signalling is dysregulated in ARID1A-KO cells, we suggest that this synthetic lethality is not due to aberrant NRF2 signalling. Rather, we find that KEAP1 perturbation exacerbates genome instability phenotypes associated with ARID1A-deficiency. Together, our findings identify a potentially novel synthetic lethal interaction of wARID1A-deficient cells.

cancer biology↗

bioRxiv2021

DYNLL1 mis-splicing is associated with replicative genome instability in SF3B1 mutant cells

Genome instability is a hallmark of cancer that arises through a panoply of mechanisms driven by oncogene and tumour-suppressor gene mutations. Oncogenic mutations in the core splicing factor SF3B1 have been linked to genome instability. Since SF3B1 mutations alter the selection of thousands of 3 splice sites affecting genes across biological pathways, it is not entirely clear how they might drive genome instability. Here we confirm that while R-loop formation and associated replication stress may account for some of the SF3B1-mutant genome instability, a mechanism involving changes in gene expression also contributes. An SF3B1-H662Q mutant cell line mis-splices the 5UTR of the DNA repair regulator DYNLL1, leading to higher DYNLL1 protein levels, mis-regulation of DNA repair pathway choice and PARP inhibitor sensitivity. Reduction of DYNLL1 protein in these cells restores genome stability. Together these data highlight how SF3B1 mutations can alter cancer hallmarks through subtle changes to the transcriptome.

cell biology↗