Biology subjects

Gloss, B. S.

Publications and source records attributed to Gloss, B. S..

5 recordsLinked to original sources

bioRxiv2025

Cumulative pregnancy and postnatal environmental exposures impact social behaviour in male mice associated with epigenetic, ribosomal, and immune dysregulation

Environmental exposures across critical developmental windows can significantly influence brain development and contribute to the pathogenesis of neurodevelopmental disorders (NDDs). Emerging clinical evidence suggests that cumulative environmental factors during early development result in more pronounced disease phenotypes in offspring. Here, we developed a triple-hit model using C57Bl/6JAusb mice to examine the cumulative effects of antenatal social stress, antenatal chronic high-fat diet consumption, and postnatal poly(I:C) exposure on neurodevelopmental outcomes in offspring. Male triple-hit offspring displayed autism-like social deficits and an overall increased susceptibility to neurodevelopmental behavioural alterations in adulthood compared to male non-stressed controls. Conversely, these behavioural changes were not observed amongst female triple-hit offspring. Single-cell RNA (scRNA) transcriptomic and bulk proteomic sequencing were performed in male triple-hit offspring across peripheral blood immune cells and brain tissue. scRNA sequencing in microglia, astrocytes, and oligodendrocytes revealed dysregulation in critical glial cell processes, ribosomal functions, and chromatin remodelling. Similar functional themes were observed across peripheral blood macrophages, neutrophils, and naive B cells - displaying immune and ribosomal dysregulation at the transcriptional level. Proteomics pathway enrichment analyses revealed significantly reduced protein abundance in ribosomal biogenesis, translation, and chromatin remodelling functions in both peripheral blood immune cells and brain tissue. We also observed synaptic dysfunction in the blood and brain proteome. Overall, using our unique triple-hit model, we demonstrate that multiple early life environmental exposures drive NDD-associated behaviours in a sex-specific manner; and is associated with overlapping central and peripheral molecular mechanisms that have clinical relevance to NDD pathogenesis.

developmental biology↗

bioRxiv2022

Bone marrow haematopoietic stem cells influence liver homeostatic networks and cancer development after dietary intervention

A holistic understanding of anti-tumor immunity requires examination of systemic immunity beyond the tumor microenvironment. This link between systemic and tumor immune activity is underexplored. We demonstrate that a stronger Type I interferon response in human liver tumors predicts better survival and correlates with the immune response in the adjacent non-tumor liver. Further, in patients with liver cancer, clonal hematopoiesis (CH) (a marker of systemic immune activation) is associated with a trend towards improved survival. In a mouse model of liver cancer, basal liver immune responses correlate with the degree of bone marrow hematopoietic stem and progenitor cell responses. A higher systemic and liver immune response, marked by innate myeloid cell infiltration reduces tumor burden, while sub-optimal systemic and liver immunity corresponded with a higher tumor burden. Our findings indicate that the state of bone marrow hematopoiesis impacts liver tumor outcomes, offering both therapeutic and prognostic opportunities.

systems biology↗

bioRxiv2019

Single-cell RNAseq uncovers involution mimicry as an aberrant development pathway during breast cancer metastasis

Both luminal and basal breast cancer subtypes originate in the mammary luminal progenitor cell compartment. Basal breast cancer is associated with younger age, early relapse, and high mortality rate. Here we used unbiased droplet-based single-cell RNAseq to elucidate the cellular basis of tumour progression during the specification of the basal breast cancer subtype from the luminal progenitor population. Basal-like cancer cells resembled the alveolar lineage that is specified upon pregnancy and showed molecular features indicative of an interaction with the tumour microenvironment (TME) including epithelial-to-mesenchymal transition (EMT), hypoxia, lactation and involution. Involution signatures in luminal breast cancer tumours with alveolar lineage features were associated with worse prognosis and features of basal breast cancer. Our high-resolution molecular characterisation of the tumour ecosystem also revealed a highly interactive cell-cell network reminiscent of an involution process. This involution mimicry involves malignant education of cancer-associated fibroblasts and myeloid cell recruitment to support tissue remodelling and sustained inflammation. Our study shows how luminal breast cancer acquires an aberrant post-lactation developmental program that involves both cancer cells and cells from the TME, to shift molecular subtype and promote tumour progression, with potential to explain the increased risk and poor prognosis of breast cancer associated to childbirth.

cancer biology↗

bioRxiv2016

Machine-learning annotation of human splicing branchpoints

BackgroundThe branchpoint element is required for the first lariat-forming reaction in splicing. However due to difficulty in experimentally mapping at a genome-wide scale, current catalogues are incomplete.\n\nResultsWe have developed a machine-learning algorithm trained with empirical human branchpoint annotations to identify branchpoint elements from primary genome sequence alone. Using this approach, we can accurately locate branchpoints elements in 85% of introns in current gene annotations. Consistent with branchpoints as basal genetic elements, we find our annotation is unbiased towards gene type and expression levels. A major fraction of introns was found to encode multiple branchpoints raising the prospect that mutational redundancy is encoded in key genes. We also confirmed all deleterious branchpoint mutations annotated in clinical variant databases, and further identified thousands of clinical and common genetic variants with similar predicted effects.\n\nConclusionsWe propose the broad annotation of branchpoints constitutes a valuable resource for further investigations into the genetic encoding of splicing patterns, and interpreting the impact of common- and disease-causing human genetic variation on gene splicing.

bioinformatics↗

bioRxiv2016

High temporal resolution of gene expression dynamics in developing mouse embryonic stem cells

Investigations of transcriptional responses during developmental transitions typically use time courses with intervals that are not commensurate with the timescales of known biological processes. Moreover, such experiments typically focus on protein-coding transcripts, ignoring the important impact of long noncoding RNAs. We evaluated coding and noncoding expression dynamics at high temporal resolution (6-hourly) in differentiating mouse embryonic stem cells and report the effects of increased temporal resolution on the characterization of the underlying molecular processes. We present a refined resolution of global transcriptional alterations, including regulatory network interactions, coding and noncoding gene expression changes as well as alternative splicing events, many of which cannot be resolved by existing coarse developmental time-{-}-courses. We describe novel short lived and cycling patterns of gene expression and temporally dissect ordered gene expression at bidirectional promoters and responses to transcription factors. These findings demonstrate the importance of temporal resolution for understanding gene interactions in mammalian systems.\n\nLinks to dataData has been deposited into GEO: The Reviewer access link is: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=cnglummejbkltyj@acc=GSE75028

systems biology↗