Biology subjects

Dighe, A.

Publications and source records attributed to Dighe, A..

5 recordsLinked to original sources

bioRxiv2023

Experimental and Phylogenetic Evidence for Correlated Gene Expression Evolution between Dermal and Endometrial Fibroblasts: implications for the evolution of cancer malignancy

Changes in transcriptional gene expression is a dominant mode of evolution, mostly driven by mutations at cis-regulatory regions. Mutations can affect gene expression in multiple cell types if the same cis-regulatory elements are used by different cell types. As a consequence, changes in gene expression in one cell type may be associated with similar gene expression changes in another cell type. Correlated gene expression change can explain correlated character evolution, as for instance the correlation between placental invasion and vulnerability to cancer malignancy. Here we test this hypothesis using a comparative and an experimental data set. Specifically, we investigate gene expression in dermal skin fibroblasts (SF) and uterine endometrial stomal fibroblasts (ESF). The comparative dataset consists of transcriptomes from cultured SF and ESF from 9 mammalian species. We calculated the independent phylogenetic contrasts (PIC) for each gene and cell type. We find that evolutionary changes in gene expression in SF and ESF are highly correlated, supporting the hypothesis that the correlated gene expression changes are a prevalent feature of gene expression evolution. The experimental data set derives from a SCID mouse strain that was selected for slow cancer growth which led to substantial changes in the SF compared to wild type SCID mice. We isolated SF and ESF from wild type and evolved SCID mice and compared their gene expression profiles. We find a significant correlation between the gene expression contrasts of SF and ESF, which supports the hypothesis that gene expression variation in SF and ESF is correlated. We discuss the implications of these findings for the hypothesized correlation between placental invasiveness and vulnerability to metastatic cancer.

evolutionary biology↗

bioRxiv2022

Proteotype Co-evolution and Diversity in Mammals

Evolutionary profiling has been largely limited to the nucleotide level. Using consistent proteomic methods, we quantified proteomic and phosphoproteomic layers in fibroblasts from 11 common mammalian species, with transcriptomic variability as reference. The co-variation analysis indicates that transcript and protein expression robustness across mammals remarkably follows functional role, with extracellular matrix-associated expressions being most variable, demonstrating strong transcriptome-proteome co-evolution. Interestingly, the variability control of gene expression is universal at both inter-individual and inter-species scales, but of different extent. RNA metabolism processes particularly show the higher inter-species versus inter-individual variations. Our results further uncover that while ubiquitin-proteasome system is extremely conserved in mammals, the lysosome-mediated protein degradation exhibits a remarkable variation between mammalian lineages. Additionally, the phosphosite profiles reveals phosphorylation co-evolution network independent of protein abundance.

systems biology↗

bioRxiv2020

Cis-Regulatory Differences Explaining Evolved Levels of Endometrial Invasibility in Eutherian Mammals

Eutherian (placental) mammals exhibit great differences in the degree of placental invasion into the maternal endometrium, with humans being on the most invasive end. Previously, we have shown that these differences in invasiveness is largely controlled by the stromal fibroblasts of the maternal endometrium, with secondary effect on stroma of other tissues resulting in correlated differences in cancer malignancy. Here, we present a statistical investigation of the second dogma linking the phenotypic and transcriptional differences to the genomic changes across species, revealing the regulatory genomic sequence differences underlying these inter-species differences. We show that gain or loss of specific transcription factor binding site sequences are connected to the inter-species gene-expression differences in a statistically significant manner, with a particularly larger effect on stromal genes related to invasibility. We also uncover transcriptional factors differentially regulating genes related to pro- and anti- invasible property of stroma. This work extends the understanding of inter-species differences in stromal invasion to the causal genomic sequence differences paving new avenues to target stromal characteristics to regulate placental, or cancer invasion.

evolutionary biology↗

bioRxiv2020

Human vulnerability to cancer malignancy is enhanced by evolution of higher mesenchymal CD44 expression compared to other mammals

CD44 is a membrane-bound extracellular matrix (ECM) receptor interacting, among others, with hyaluronic acid (HA) and osteopontin (OPN). Cancer progression and metastasis are greatly influenced by the cancer micro-environment, consisting of ECM, immune cells and cancer-associated fibroblasts (CAF). Recruitment of fibroblasts (FB) into the role as CAFs is caused by paracrine signals from the tumor, including TGFb1, PDGF and OPN. The effect of OPN on the transformation of FB into CAF is mediated by CD44. CD44 expression in human skin and endometrial stromal fibroblasts (SF and ESF, respectively) also enhances invasibility of stroma by trophoblast as well as cancer cells. Here we study the evolution of CD44 expression in therian mammals in both SF as well as ESF and demonstrate that the human lineage has experienced a concerted evolutionary enhancement of CD44 expression in SF and ESF, correlating with an increase in human vulnerability to cancer malignancy. In both human and cattle (Bos taurus), the dominant isoforms are CD44s and CD44v10 with 9 and 10 exons, respectively. CD44s is an isoform strongly associated with malignancy. In humans, an additional isoform is expressed: HsaCD44-205 with 8 exons not found in cattle. We show that the concerted increase of CD44 expression in SF and ESF is largely due to cis-regulatory effects in the proximal promoter of CD44. We identify a primate specific acquisition of CEBPB binding sites in the CD44 promoter. Recruitment of CEBPB into CD44 regulation explains almost 50% of the lineage-specific increased CD44 expression in primate skin fibroblasts but is not necessary for high CD44 expression in ESF. All these results suggest that selective modulation of CD44 expression in skin fibroblasts could attenuate the cancer-promoting effect of CAF recruitment in the skin with minimal side effects on other cell types. Additional experimental data is needed to explore this possibility.

evolutionary biology↗

bioRxiv2019

A systematic review of MERS-CoV (Middle East Respiratory Syndrome Coronavirus) seroprevalence and viral RNA prevalence in dromedary camels: implications for animal vaccination

Human infection with Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is driven by recurring dromedary-to-human spill-over events, leading decision-makers to consider dromedary vaccination. Dromedary vaccine candidates in the development pipeline are showing hopeful results, but gaps in our understanding of the epidemiology of MERS-CoV in dromedaries must be addressed to design and evaluate potential vaccination strategies. We systematically reviewed the published literature reporting seroprevalence and/or prevalence of active MERS-CoV infection in dromedary populations from both cross-sectional and longitudinal studies, including 60 studies in our qualitative syntheses. MERS-CoV seroprevalence increased with age up to 80-100% in adult dromedaries supporting geographically wide spread endemicity of MERS-CoV in dromedaries in both the Arabian Peninsula and countries exporting dromedaries from Africa. The high prevalence of active infection measured in juveniles and at sites where dromedary populations mix should guide further investigation - particularly of dromedary movement - and inform vaccination strategy design.

epidemiology↗