Biology subjects

Joshi, P.

Publications and source records attributed to Joshi, P..

4 recordsLinked to original sources

bioRxiv2018

Developmental Regulation of an Organelle Tether Coordinates Mitochondrial Remodeling in Meiosis

Cellular differentiation involves remodeling cellular architecture to transform one cell type to another. By investigating mitochondrial dynamics during meiotic differentiation in budding yeast, we sought to understand how organelle morphogenesis is developmentally controlled in a system where regulators of differentiation as well as organelle architecture are known, but the interface between them remains unexplored. We found that mitochondria abruptly detach from the cell cortex shortly before segregating into gametes. Mitochondrial detachment is enabled by the programmed destruction of the mitochondria-endoplasmic reticulum-cortex anchor (MECA), an organelle tether that forms contact sites between mitochondria and the plasma membrane. MECA regulation is governed by a meiotic transcription factor, Ndt80, which promotes the activation of a conserved kinase, Ime2. We found that MECA undergoes Ime2-dependent phosphorylation. Furthermore, Ime2 promotes MECA degradation in a temporally controlled manner. Our study defines a key mechanism that coordinates mitochondrial morphogenesis with the landmark events of meiosis and demonstrates that cells can developmentally regulate tethering to induce organelle remodeling.

cell biology↗

bioRxiv2018

Genomic underpinnings of lifespan allow prediction and reveal basis in modern risks

We use a multi-stage genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near GADD45G, KCNK3, LDLR, POM121C, ZC3HC1, and ABO. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and tissue-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer -but not other cancers-explain the most variance, possibly reflecting modern susceptibilities, whilst cancer may act through many rare variants, or the environment. Resultant polygenic scores predict a mean lifespan difference of around five years of life across the deciles.

genomics↗

bioRxiv2017

Cdx4 regulates the onset of spinal cord neurogenesis

The progressive maturation of cells down differentiation lineages is controlled by collaborative interactions between networks of extracellular signals and intracellular transcription factors. In the vertebrate spinal cord, FGF, Wnt and Retinoic Acid signaling pathways regulate the progressive caudal-to-rostral maturation of neural progenitors by regulating a poorly understood gene regulatory network of transcription factors. We have mapped out this gene regulatory network in the chicken pre-neural tube, identifying CDX4 as a dual-function core component that simultaneously regulates gradual loss of cell potency and acquisition of differentiation states: in a caudal-to-rostral direction, CDX4 represses the early neural differentiation marker Nkx1.2 and promotes the late neural differentiation marker Pax6. Significantly, CDX4 prevents premature PAX6-dependent neural differentiation by blocking Ngn2 activation. This regulation of CDX4 over Pax6 is restricted to the rostral pre-neural tube by Retinoic Acid signaling. Together, our results show that in the spinal cord, CDX4 is part of the gene regulatory network controlling the sequential and progressive transition of states from high to low potency during neural progenitor maturation. Given CDX well-known involvement in Hox gene regulation, we propose that CDX factors coordinate the maturation and axial specification of neural progenitor cells during spinal cord development.

developmental biology↗

bioRxiv2017

Novel Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk Of Coronary Artery Disease

Structural variation in retinal blood vessels is associated with global vascular health in humans and may provide a readily accessible indicator of several diseases of vascular origin. Increasing evidence suggests variation in retinal vasculature is highly heritable. This study aimed to identify genetic determinants of retinal vascular traits. We reported a meta-analysis of genome-wide association studies (GWAS) for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the Genetics of Diabetes Audit and Research in Tayside (GoDARTS) (n=1736) and the Orkney Complex Disease Study (ORCADES) (n=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (ACTN4/CAPN12) for retinal venular tortuosity (TortV), and one at 13q34 (COL4A2) for retinal arteriolar tortuosity (TortA); these two loci were subsequently confirmed in three independent cohorts (n=1413). In the combined analysis in ACTN4/CAPN12 the lead single nucleotide polymorphism (SNP) was rs1808382 (n=4507; Beta=-0.109; standard error (SE) =0.015; P=2.39x10-13) and in COL4A2 it was rs7991229 (n=4507; Beta=0.103; SE=0.015; P=4.66x10-12). Notably, the ACTN4/CAPN12 locus associated with retinal TortV is also associated with coronary artery disease and heart rate. Our findings demonstrate the contribution of genetics in retinal tortuosity traits, and provide new insights into cardiovascular diseases.\n\nAuthor SummaryRetinal vascular features are associated with wide range of diseases related to vascular health and provide an opportunity to understand early structural changes in vasculature which may help to predict disease risk. Emerging evidence indicates that retinal tortuosity traits are both associated with vascular health and highly heritable. However, the genetic architecture of retinal vascular tortuosity has not been investigated. We therefore performed a genome-wide association study on retinal arteriolar tortuosity (TortA) and retinal venular tortuosity trait (TortV) using data from two independent discovery cohorts of 3094 individuals of European-heritage. We found a novel associations at 19q13 (ACTN4/CAPN12) for TortV, and one at 13q34 (COL4A2) for TortA at discovery stage and validated in three independent cohorts. A significant association was subsequently found between lead SNPs at 19q13 and coronary artery disease, cardiovascular vascular risk factors and heart rate. We also performed genome-wide association studies for retinal vascular calibres and optic disc radius (ODradius) and replicated previously reported locus at 10q21.3 for ODradius. Our findings highlight genetic impacts on retinal venular tortuosity and it is association with cardiovascular disease. This may provide a molecular pathophysiological foundation for use of retinal vascular traits as biomarkers for cardiovascular diseases.

genomics↗