Biology subjects

Chandra, T.

Publications and source records attributed to Chandra, T..

24 records · Page 2Linked to original sources

bioRxiv2019

An epigenome-wide association study of sex-specific chronological ageing

IntroductionAdvanced age is associated with cognitive and physical decline, and is a major risk factor for a multitude of disorders including neurodegenerative diseases such as Alzheimers disease. There is also a gap in life-expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in DNA methylation in an unrelated cohort of 2,586 individuals between the ages of 18 and 87 years.\n\nMethodsGenome-wide DNA methylation was measured on the Illumina HumanMethylationEPIC beadchip in a subset of unrelated individuals from the Generation Scotland cohort. Mixed linear model-based analyses were performed to investigate the relationship between DNA methylation and an interaction term between age and sex, as well as chronological age.\n\nResultsAt a genome-wide significance level of P < 3.6 x 10-8, 14 loci were associated with the age-by-sex interaction term, the majority of which were X-linked (n = 12). Seven of these loci were annotated to genes. The site with the greatest difference mapped to GAGE10, an X-linked gene. Here, DNA methylation levels remained stable across the male adult age range (DNA methylation x age r = 0.02), but decreased across female adult age range (DNA methylation x age r = -0.61). The seven age-by-sex-associated genes were enriched among differentially-expressed genes in lung, liver, testis and blood.\n\nConclusionThe majority of differences in age-associated DNA methylation trajectories between sexes are present on the X-chromosome. Several of these differences occur within genes which have implicated in multiple cancers, schizophrenia and systemic lupus erythematosus.

genomics↗

bioRxiv2019

Age-related clonal haemopoiesis is associated with increased epigenetic age

Age-related clonal haemopoiesis (ARCH) in healthy individuals was initially observed through an increased skewing in X chromosome inactivation. More recently, several groups reported that ARCH is driven by somatic mutations. The most prevalent ARCH mutations are in the DNMT3A and TET2 genes, previously described as drivers of myeloid malignancies. ARCH is associated with an increased risk for haematological cancers. ARCH also confers an increased risk for non-haematological diseases such as cardiovascular disease, atherosclerosis, and chronic ischemic heart failure, for which age is a main risk factor. Whether ARCH is linked to accelerated ageing has remained unexplored. The most accurate and commonly-used tools to measure age acceleration are epigenetic clocks. They are based on age-related methylation differences at specific CpG sites correlating chronological age accurately with epigenetic age. Deviations from chronological age towards an increased epigenetic age have been associated with increased risk of earlier mortality and age-related morbidities. Here we present evidence of accelerated epigenetic age in individuals with ARCH.

bioinformatics↗

bioRxiv2019

Notch signalling mediates secondary senescence

Oncogene induced senescence (OIS) is a tumour suppressive response to oncogene activation that can be transmitted to neighbouring cells through secreted factors of the senescence associated secretory phenotype (SASP). Using single-cell transcriptomics we observed two distinct endpoints, a primary marked by Ras and a secondary by Notch. We find that secondary senescence in vitro and in vivo requires Notch, rather than SASP alone as previously thought. Currently, primary and secondary senescent cells are not thought of as functionally distinct endpoints. A blunted SASP response and the induction of fibrillar collagens in secondary senescence compared to OIS point towards a functional diversification. One Sentence SummaryNotch signalling is an essential driver of secondary senescence with primary and secondary senescence being distinct molecular endpoints.

genomics↗

bioRxiv2018

Lamina and Heterochromatin Direct Chromosome Organisation in Senescence and Progeria

Lamina-associated domains (LADs) cover a large part of the human genome and are thought to play a major role in shaping the nuclear architectural landscape. Here, we use simulations based on concepts from polymer physics to dissect the roles played by heterochromatin- and lamina-mediated interactions in nuclear organisation. Our model explains the conventional organisation of heterochromatin and euchromatin in growing cells, as well as the pathological organisation found in oncogene-induced senescence and progeria. We show that the experimentally observed changes in the locality of contacts in senescent and progeroid cells can be explained naturally as arising due to phase transitions in the system. Our model predicts that LADs are highly stochastic, and that, once established, the senescent phenotype should be metastable even if lamina-mediated interactions were reinstated. Overall, our simulations uncover a universal physical mechanism that can regulate heterochromatin segregation and LAD formation in a wide range of mammalian nuclei.

biophysics↗

bioRxiv2018

Inhibition of the 60S ribosome biogenesis GTPase LSG1 causes endoplasmic reticular disruption and cellular senescence

Cellular senescence is triggered by diverse stimuli and is characterised by long-term growth arrest and secretion of cytokines and chemokines (termed the SASP - senescence-associated secretory phenotype). Senescence can be organismally beneficial as it can prevent the propagation of damaged or mutated clones and stimulate their clearance by immune cells. However, it has recently become clear that senescence also contributes to the pathophysiology of aging through the accumulation of damaged cells within tissues. Here we describe that inhibition of the reaction catalysed by LSG1, a GTPase involved in the biogenesis of the 60S ribosomal subunit, leads to a robust induction of cellular senescence. Perhaps surprisingly, this was not due to ribosome depletion or translational insufficiency, but rather through perturbation of endoplasmic reticulum (ER) homeostasis and a dramatic upregulation of the cholesterol biosynthesis pathway. This cholesterol/ER signature is shared with several other forms of senescence and contributes to the cell cycle arrest in oncogene-induced senescence (OIS). Furthermore, targetting of LSG1 resulted in amplification of the cholesterol/ER signature and restoration of a robust cellular senescence response in transformed cells, suggesting potential therapeutic uses of LSG1 inhibition.

cancer biology↗

bioRxiv2018

Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity

Induced pluripotent stem cells (IPSCs), with their unlimited regenerative capacity, carry the promise for tissue replacement to counter age-related decline. However, attempts to realise in vivo iPSC have invariably resulted in the formation of teratomas. Partial reprogramming in prematurely aged mice has shown promising results in alleviating age-related symptoms without teratoma formation. Does partial reprogramming lead to rejuvenation (i.e. \"younger\" cells), rather than dedifferentiation, which bears the risk of cancer? Here we analyse the dynamics of cellular age during human iPSC reprogramming and find that partial reprogramming leads to a reduction in the epigenetic age of cells. We also find that the loss of somatic gene expression and epigenetic age follow different kinetics, suggesting that they can be uncoupled and there could be a safe window where rejuvenation can be achieved with a minimised risk of cancer.

developmental biology↗