Biology subjects

Dhaliwal, J.

Publications and source records attributed to Dhaliwal, J..

4 recordsLinked to original sources

bioRxiv2024

Accessible chromatin maps of inflammatory bowel disease intestine nominate cell-type mediators of genetic disease risk

Inflammatory Bowel Disease (IBD) is a chronic autoinflammatory disorder with rising incidence in pediatrics. TNFa inhibition (TNFi) is the first-line biologic therapy in children, but many do not achieve mucosal healing. Identifying which patients will benefit from TNFi and the underlying nonresponse mechanisms is critical. We built a novel resource: whole genome sequencing linked to multiome-seq (single-nuclei transcriptome and chromatin accessibility) of intestinal biopsies from a cohort of children with IBD, whose TNFi response was defined by mucosal healing. Our study uncovers links between IBD genetic risk and TNFi response. First, classifiers integrating genetic data with clinical variables identified the IBD polygenic risk score as a top predictor of TNFi response. Second, multiome-seq analysis implicated IBD risk variants in persistent cytokine signaling in monocytes, macrophage and fibroblasts of nonresponders. These data reveal genetic mechanisms of treatment response in pediatric IBD and suggest alternative therapeutic approaches for TNFi nonresponders.

genomics↗

bioRxiv2024

Mitotic Activity and DNA Maintenance of Adult Neural Stem Cells is Regulated by Beclin1

Beclin1 is a tumor suppressor gene that can regulate proliferation under pathological conditions. Whether Beclin1 has a role in regulating proliferation in physiological conditions remains unknown. Here, through the creation of an inducible transgenic mouse that removes Beclin1 from adult neural stem and progenitor cells (NSPCs) and their progeny we uncovered that Beclin1 is required cell-autonomously to sustain proliferating NSCPs in vivo and ex vivo. Flow cytometry analysis and single-cell RNA-sequencing show that Beclin1 is required for mitosis. Additional analysis of the proliferating NSPCs resolved by stage of cell cycle uncovered that Beclin1-null cells have a distinct differential developmental trajectory accompanied by downregulation of genes involved in chromosomal maintenance and upregulation of cell stress genes upon cell cycle exit. These effects align with DNA damage in Beclin1-null cells and ultimately result in less adult-born granular neurons. Together these data identify Beclin1 as a novel regulator of mitosis in adult NSPCs.

neuroscience↗

bioRxiv2023

Neurogenesis-mediated circuit remodeling reduces engram reinstatement and promotes forgetting

Post-training increases in hippocampal neurogenesis are associated with forgetting of hippocampus-dependent memories in adult mice. This form of forgetting might be due to increased numbers of new neurons, remodeling of hippocampal circuitry or some combination of both. Here we tested the hypothesis that neurogenesis-mediated forgetting is caused by remodeling of hippocampal circuits by engineering mice in which adult-generated granule cells hypo- or hyper-integrate into hippocampal circuits. Using gene deletion, opto- and chemogenetic strategies, we find that hypo-integration of newborn neurons prevents post- training exercise-induced forgetting of contextual fear memories. Conversely, inducing hyper- integration of newborn neurons following contextual fear conditioning is sufficient to produce forgetting. Because these interventions did not affect survival of newborn neurons, these findings suggest that neurogenesis-mediated remodeling of hippocampal circuits represents a continuous and active form of interference that alters accessibility of engrams underlying hippocampal memories. Consistent with this, using engram-labeling approaches, we found that exercise-induced forgetting was associated with reduced engram reactivation.

neuroscience↗

bioRxiv2021

Chloroplast-localized translation for protein targeting in Chlamydomonas reinhardtii

Translation is localized within cells to target proteins to their proper locations. We asked whether translation occurs on the chloroplast surface in Chlamydomonas and, if so, whether it is involved in co-translational protein targeting, aligned spatially with localized translation by the bacterial-type ribosomes within this organelle, or both. Our results reveal a domain of the chloroplast envelope which is bound by translating ribosomes. Purified chloroplasts retained ribosomes and mRNAs encoding two chloroplast proteins specifically on this "translation domain", but not a mRNA encoding a cytoplasmic protein. Ribosomes clusters were seen on this domain by electron tomography. Activity of the chloroplast-bound ribosomes is supported by results of the ribopuromycylation and puromycin-release assays. Co-translational chloroplast protein import is supported by nascent polypeptide dependency of the ribosome-chloroplast associations. This cytoplasmic translation domain aligns localized translation by organellar bacterial-type ribosomes in the chloroplast. This juxtaposition the dual translation systems facilitates the targeting and assembly of the polypeptide products. One-Sentence SummaryTranslation is localized to a domain of the chloroplast envelope for co-translational protein targeting in Chlamydomonas.

cell biology↗