Publications by authors named "Aditya Sankar"

9 Publications

  • Page 1 of 1

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611832PMC
August 2021

PR-DUB maintains the expression of critical genes through FOXK1/2- and ASXL1/2/3-dependent recruitment to chromatin and H2AK119ub1 deubiquitination.

Genome Res 2020 08 3;30(8):1119-1130. Epub 2020 Aug 3.

Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark.

Polycomb group proteins are important for maintaining gene expression patterns and cell identity in metazoans. The mammalian Polycomb repressive deubiquitinase (PR-DUB) complexes catalyze removal of monoubiquitination on lysine 119 of histone H2A (H2AK119ub1) through a multiprotein core comprised of BAP1, HCFC1, FOXK1/2, and OGT in combination with either of ASXL1, 2, or 3. Mutations in PR-DUB components are frequent in cancer. However, mechanistic understanding of PR-DUB function in gene regulation is limited. Here, we show that BAP1 is dependent on the ASXL proteins and FOXK1/2 in facilitating gene activation across the genome. Although PR-DUB was previously shown to cooperate with PRC2, we observed minimal overlap and functional interaction between BAP1 and PRC2 in embryonic stem cells. Collectively, these results demonstrate that PR-DUB, by counteracting accumulation of H2AK119ub1, maintains chromatin in an optimal configuration ensuring expression of genes important for general functions such as cell metabolism and homeostasis.
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http://dx.doi.org/10.1101/gr.261016.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462075PMC
August 2020

KDM4A regulates the maternal-to-zygotic transition by protecting broad H3K4me3 domains from H3K9me3 invasion in oocytes.

Nat Cell Biol 2020 04 30;22(4):380-388. Epub 2020 Mar 30.

DNRF Center for Chromosome Stability (CCS), Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The importance of germline-inherited post-translational histone modifications on priming early mammalian development is just emerging. Histone H3 lysine 9 (H3K9) trimethylation is associated with heterochromatin and gene repression during cell-fate change, whereas histone H3 lysine 4 (H3K4) trimethylation marks active gene promoters. Mature oocytes are transcriptionally quiescent and possess remarkably broad domains of H3K4me3 (bdH3K4me3). It is unknown which factors contribute to the maintenance of the bdH3K4me3 landscape. Lysine-specific demethylase 4A (KDM4A) demethylates H3K9me3 at promoters marked by H3K4me3 in actively transcribing somatic cells. Here, we report that KDM4A-mediated H3K9me3 demethylation at bdH3K4me3 in oocytes is crucial for normal pre-implantation development and zygotic genome activation after fertilization. The loss of KDM4A in oocytes causes aberrant H3K9me3 spreading over bdH3K4me3, resulting in insufficient transcriptional activation of genes, endogenous retroviral elements and chimeric transcripts initiated from long terminal repeats during zygotic genome activation. The catalytic activity of KDM4A is essential for normal epigenetic reprogramming and pre-implantation development. Hence, KDM4A plays a crucial role in preserving the maternal epigenome integrity required for proper zygotic genome activation and transfer of developmental control to the embryo.
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http://dx.doi.org/10.1038/s41556-020-0494-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212036PMC
April 2020

Towards AR-assisted visualisation and guidance for imaging of dental decay.

Healthc Technol Lett 2019 Dec 26;6(6):243-248. Epub 2019 Nov 26.

Human Photonics Lab, Department of Mechanical Engineering, University of Washington, Seattle, WA 98195, USA.

Untreated dental decay is the most prevalent dental problem in the world, affecting up to 2.4 billion people and leading to a significant economic and social burden. Early detection can greatly mitigate irreversible effects of dental decay, avoiding the need for expensive restorative treatment that forever disrupts the enamel protective layer of teeth. However, two key challenges exist that make early decay management difficult: unreliable detection and lack of quantitative monitoring during treatment. New optically based imaging through the enamel provides the dentist a safe means to detect, locate, and monitor the healing process. This work explores the use of an augmented reality (AR) headset to improve the workflow of early decay therapy and monitoring. The proposed workflow includes two novel AR-enabled features: (i) in situ visualisation of pre-operative optically based dental images and (ii) augmented guidance for repetitive imaging during therapy monitoring. The workflow is designed to minimise distraction, mitigate hand-eye coordination problems, and help guide monitoring of early decay during therapy in both clinical and mobile environments. The results from quantitative evaluations as well as a formative qualitative user study uncover the potentials of the proposed system and indicate that AR can serve as a promising tool in tooth decay management.
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http://dx.doi.org/10.1049/htl.2019.0082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952244PMC
December 2019

The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis.

J Diabetes Res 2019 28;2019:5451038. Epub 2019 Jul 28.

Immuno-endocrinology Laboratory, Department of Biomedical Sciences, University of Copenhagen, Denmark.

Aims: Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function.

Materials And Methods: We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B.

Results: GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice.

Conclusion: Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.
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http://dx.doi.org/10.1155/2019/5451038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701283PMC
January 2020

Maternal expression of the histone demethylase Kdm4a is crucial for pre-implantation development.

Development 2017 09 21;144(18):3264-3277. Epub 2017 Aug 21.

Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen 2200, Denmark

Regulation of chromatin composition through post-translational modifications of histones contributes to transcriptional regulation and is essential for many cellular processes, including differentiation and development. KDM4A (JMJD2A) is a lysine demethylase with specificity towards di- and tri-methylated lysine 9 and lysine 36 of histone H3 (H3K9me2/me3 and H3K36me2/me3). Here, we report that as a maternal factor plays a key role in embryo survival and is vital for female fertility. female mice ovulate normally with comparable fertilization but poor implantation rates, and cannot support healthy transplanted embryos to term. This is due to a role for Kdm4a in uterine function, where its loss causes reduced expression of key genes involved in ion transport, nutrient supply and cytokine signalling, which impact embryo survival. In addition, a significant proportion of Kdm4a-deficient oocytes displays a poor intrinsic ability to develop into blastocysts. These embryos cannot compete with healthy embryos for implantation , highlighting as a maternal effect gene. Thus, our study dissects an important dual role for maternal Kdm4a in determining faithful early embryonic development and the implantation process.
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http://dx.doi.org/10.1242/dev.155473DOI Listing
September 2017

ZFP57 maintains the parent-of-origin-specific expression of the imprinted genes and differentially affects non-imprinted targets in mouse embryonic stem cells.

Nucleic Acids Res 2016 09 1;44(17):8165-78. Epub 2016 Jun 1.

Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, 80131 Naples, Italy Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, 81100 Caserta, Italy

ZFP57 is necessary for maintaining repressive epigenetic modifications at Imprinting control regions (ICRs). In mouse embryonic stem cells (ESCs), ZFP57 binds ICRs (ICRBS) and many other loci (non-ICRBS). To address the role of ZFP57 on all its target sites, we performed high-throughput and multi-locus analyses of inbred and hybrid mouse ESC lines carrying different gene knockouts. By using an allele-specific RNA-seq approach, we demonstrate that ZFP57 loss results in derepression of the imprinted allele of multiple genes in the imprinted clusters. We also find marked epigenetic differences between ICRBS and non-ICRBS suggesting that different cis-acting regulatory functions are repressed by ZFP57 at these two classes of target loci. Overall, these data demonstrate that ZFP57 is pivotal to maintain the allele-specific epigenetic modifications of ICRs that in turn are necessary for maintaining the imprinted expression over long distances. At non-ICRBS, ZFP57 inactivation results in acquisition of epigenetic features that are characteristic of poised enhancers, suggesting that another function of ZFP57 in early embryogenesis is to repress cis-acting regulatory elements whose activity is not yet required.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041456PMC
http://dx.doi.org/10.1093/nar/gkw505DOI Listing
September 2016

SWI/SNF Subunits SMARCA4, SMARCD2 and DPF2 Collaborate in MLL-Rearranged Leukaemia Maintenance.

PLoS One 2015 16;10(11):e0142806. Epub 2015 Nov 16.

Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.

Alterations in chromatin structure caused by deregulated epigenetic mechanisms collaborate with underlying genetic lesions to promote cancer. SMARCA4/BRG1, a core component of the SWI/SNF ATP-dependent chromatin-remodelling complex, has been implicated by its mutational spectrum as exerting a tumour-suppressor function in many solid tumours; recently however, it has been reported to sustain leukaemogenic transformation in MLL-rearranged leukaemia in mice. Here we further explore the role of SMARCA4 and the two SWI/SNF subunits SMARCD2/BAF60B and DPF2/BAF45D in leukaemia. We observed the selective requirement for these proteins for leukaemic cell expansion and self-renewal in-vitro as well as in leukaemia. Gene expression profiling in human cells of each of these three factors suggests that they have overlapping functions in leukaemia. The gene expression changes induced by loss of the three proteins demonstrate that they are required for the expression of haematopoietic stem cell associated genes but in contrast to previous results obtained in mouse cells, the three proteins are not required for the expression of c-MYC regulated genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142806PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646637PMC
June 2016

The endonuclease activity of Mili fuels piRNA amplification that silences LINE1 elements.

Nature 2011 Oct 23;480(7376):259-63. Epub 2011 Oct 23.

European Molecular Biology Laboratory, Mouse Biology Unit, Via Ramarini 32, Monterotondo Scalo 00015, Italy.

Piwi proteins and Piwi-interacting RNAs (piRNAs) have conserved functions in transposon silencing. The murine Piwi proteins Mili and Miwi2 (also called Piwil2 and Piwil4, respectively) direct epigenetic LINE1 and intracisternal A particle transposon silencing during genome reprogramming in the embryonic male germ line. Piwi proteins are proposed to be piRNA-guided endonucleases that initiate secondary piRNA biogenesis; however, the actual contribution of their endonuclease activities to piRNA biogenesis and transposon silencing remain unknown. To investigate the role of Piwi-catalysed endonucleolytic activity, we engineered point mutations in mice that substitute the second aspartic acid to an alanine in the DDH catalytic triad of Mili and Miwi2, generating the Mili(DAH) and Miwi2(DAH) alleles, respectively. Analysis of Mili-bound piRNAs from homozygous Mili(DAH) fetal gonadocytes revealed a failure of transposon piRNA amplification, resulting in the marked reduction of piRNA bound within Miwi2 ribonuclear particles. We find that Mili-mediated piRNA amplification is selectively required for LINE1, but not intracisternal A particle, silencing. The defective piRNA pathway in Mili(DAH) mice results in spermatogenic failure and sterility. Surprisingly, homozygous Miwi2(DAH) mice are fertile, transposon silencing is established normally and no defects in secondary piRNA biogenesis are observed. In addition, the hallmarks of piRNA amplification are observed in Miwi2-deficient gonadocytes. We conclude that cycles of intra-Mili secondary piRNA biogenesis fuel piRNA amplification that is absolutely required for LINE1 silencing.
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http://dx.doi.org/10.1038/nature10547DOI Listing
October 2011
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