<p><strong>Genome Instability in Aging and Disease</strong></p>
<p>Genome instability, i.e., the tendency of the genome to acquire mutations and epimutations, underlies human genetic disease, causally contributes to cancer and has also been implicated in aging and age-related, degenerative conditions other than cancer. Little is known about the mechanisms that give rise to spontaneous changes in the genome or epigenome and how this may lead, in somatic cells, to increased cancer risk and loss of organ and tissue function with age. We study genome and epigenome instability as a function of age in various model organisms, including mouse and fruit fly, and its consequences in terms of alterations in tissue-specific patterns of gene regulation.</p>
<p>In the past we developed transgenic reporter systems in mouse and fruit fly, which allowed us to determine tissue-specific frequencies of various forms of genome instability, e.g., point mutations, deletions, translocations. By crossing the mutational reporter animals with mutants harboring specific defects in various genome maintenance pathways, the relevance of these pathways for the accumulation of specific forms of genome instability is assessed, in relation to the pathophysiology of aging. Similarly, by using knockdown approaches we assess the effect of specific genes implicated in longevity and healthy aging, e.g., SOD, FOXO, SIR2, on genome integrity.</p>
<p>We are currently focused on single-cell genomics to assess mutation frequencies and spectra in human tissues during aging. To gain insight into the possible functional consequences of random somatic mutations we use single-cell multiomics assays to link specific mutations to transcriptional and translational end point.&nbsp;</p>
<p><strong>Projects</strong></p>
<p><a href="http://einstein.yu.edu/departments/genetics/research/aging-program-proj… Program Project</a></p>
<p><strong> People</strong></p>
<ul>
<li>Yolanne Blake</li>
<li>Shixiang Sun</li>
<li>Moonsook Lee</li>
<li>Zhenqiu Huang</li>
<li>Alex Maslov</li>
<li>Johanna Heid</li>
<li>Yujue Wang</li>
<li>Julian Gingold</li>
<li>Olivia Albert</li>
<li>Ronald Cutler</li>
</ul>

<p class="MsoNormal" style="line-height: 15.6pt;"><span style="font-size: 9.0pt;">Dr. Vijg studies the molecular genetic changes associated with aging. Instability of genome and epigenome &ndash; the entire set of an organism&rsquo;s genes and the switches that control their activity &ndash;&nbsp; has long been implicated as the main cause of cancer and of the loss of organ and tissue function associated with aging.</span></p>
<p class="MsoNormal" style="line-height: 15.6pt;"><span style="font-size: 9.0pt;">Dr. Vijg&rsquo;s research team was the first to develop a transgenic animal model for studying how mutations in human genes affect aging in a living organism. Since then, he has developed new versions of this mouse model that aid researchers in monitoring ongoing changes in DNA in different tissues or during various developmental stages over the course of the lifespan. Currently, Dr. Vijg uses next-generation sequencing to directly quantify and characterize mutations and epimutations in cells and tissues of aging organisms. An important component of these studies is the development of new methods for analyzing genome and epigenome in single cells to better understand intra-tissue heterogeneity during aging and in relation to cancer.</span></p>

<p><strong>Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA, Dollé MET, Calder RB, Chisholm GB, Pollock BH, Klein CA, Vijg J.</strong> Increased cell-to-cell variation in gene expression in aging mouse heart. <em>Nature</em> 2006;441:1011-1014.</p>
<p><strong>Vijg J, Campisi J.</strong> Puzzles, promises and a cure for ageing. <em>Nature</em> 2008;454: 1065.<br>
<strong>White RR, Milholland B, de Bruin A, Curran S, Laberge RM, van Steeg H, Campisi J, Maslov AY, Vijg J. </strong>Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing. Nat Commun. 2015;6:6790.</p>
<p><strong>Gravina S, Dong X, Yu B, Vijg J.</strong> Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome. Genome Biol. 2016;17:150.</p>
<p><strong>Dong X, Milholland B, Vijg J.</strong> Evidence for a limit to human lifespan. Nature 2016; 538:257–259. PMID:27706136.</p>
<p><strong>Dong X, Zhang L, Milholland B, Lee M, Maslov AY, Wang T, Vijg J.</strong> Accurate identification of single-nucleotide variants in whole-genome-amplified single cells. Nat Methods 2017;14:491-493. PMC5408311</p>
<p><strong>Zhang L, Dong X, Lee M, Maslov AY, Wang T, Vijg J.</strong> Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan. Proc Natl Acad Sci USA 2019;116:9014-9019. PMC650011</p>
<p><strong>Brazhnik K, Sun S, Alani O, Kinkhabwala M, Wolkoff AW, Maslov AY, Dong X, Vijg J.</strong> Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver. Sci Adv. 2020;6:eaax2659. PMC6994209</p>
<p><strong>Vijg J, Dong X</strong>. Pathogenic Mechanisms of Somatic Mutation and Genome Mosaicism in Aging. Cell 2020;18:12-23.</p>
<p><strong>Zhang L, Dong X, Tian X, Lee M, Ablaeva J, Firsanov D, Lee S-G, Maslov AY, Gladyshev VN, Seluanov A, Gorbunova V, Vijg J.</strong> Maintenance of genome sequence integrity in long- and short-lived rodent species. Sci Adv 2021;7:eabj3284. PMC8550225</p>
<p><strong>Huang Z, Sun S, Lee M, Maslov AY, Shi M, Waldman S, Marsh A, Siddiqui T, Dong X, Peter Y, Sadoughi A, Shah C, Ye K, Spivack SD, Vijg J.</strong> Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking. Nat. Genet. 2022;54:492-498. </p>
<p> </p>

<p>Our research is based on understanding models of genetic susceptibility to human disease, especially those affecting children.</p>
<p>We focus on understanding phenotypes, through genetic or environmental influences that change the innate properties of a canonical cell type, or how those influences alter cell lineage choices during differentiation.</p>
<p>Our studies are facilitated by Einstein's Center for Epigenomics, its Epigenomics Shared Facility and the Computational Epigenomics Group.</p>
<p>Our basic research involves the study of the effects of environmental and genetic influences on stem cell differentiation, with a focus on liver and blood diseases.</p>
<p>Our lab is focusing on stem cell systems to understand mechanisms of cellular memory, and to reveal the functional variants in the non-coding majority of the human genome.</p>
<p>Our clinical research program is centered on the New York Center for Rare Diseases, where we contribute to advanced diagnostics through long-read sequencing and advanced phenotyping and analytical tools.</p>

<p class="MsoNormal" style="line-height: 15.6pt;"><span style="font-size: 9.0pt;">Dr. Greally began his career as a pediatrician who subspecialized in clinical genetics, seeing patients with genetic syndromes, birth defects and developmental problems. Now, Dr. Greally seeks to understand how genetic disease is caused not by DNA mutations, but due to abnormalities in how genes are switched off and on &ndash; a field known as epigenomics.&nbsp;</span></p>
<p class="MsoNormal" style="line-height: 15.6pt;"><span style="font-size: 9.0pt;">Dr. Greally&rsquo;s research focuses on epigenetic abnormalities in human diseases such as breast cancer, type 2 diabetes, viral hepatitis, and allergies and on epigenetic regulation of stem cell differentiation. He also serves on the editorial board of the journal<span>&nbsp;</span><em>Epigenetics &amp; Chromatin</em>.&nbsp;</span></p>

<p>Rosean S, Sosa EA, O'Shea D, Raj SM, Seoighe C, <strong>Greally JM</strong>. Regulatory landscape enrichment analysis (RLEA): a computational toolkit for non-coding variant enrichment and cell type prioritization. <strong><em>BMC Bioinformatics</em></strong>. 2024 May 7;25(1):179. doi: 10.1186/s12859-024-05794-7. PMID: 38714913; PMCID: PMC11075237.</p>
<p>Pearson NM, Stolte C, Shi K, Beren F, Abul-Husn NS, Bertier G, Brown K, Diaz GA, Odgis JA, Suckiel SA, Horowitz CR, Wasserstein M, Gelb BD, Kenny EE, Gagnon C, Jobanputra V, Bloom T, Greally JM. GenomeDiver: a platform for phenotype-guided medical genomic diagnosis. Genet Med. 2021 Oct;23(10):1998-2002. doi: 10.1038/s41436-021-01219-5. Epub 2021 Jun 10. PMID: 34113009; PMCID: PMC8488006.</p>
<p>Johnston AD, Simões-Pires CA, Thompson TV, Suzuki M, Greally JM. Functional genetic variants can mediate their regulatory effects through alteration of transcription factor binding. Nat Commun. 2019 Aug 2;10(1):3472. doi: 10.1038/s41467-019-11412-5. PMID: 31375681; PMCID: PMC6677801.</p>
<p>Sato H, Wu B, Delahaye F, Singer RH, Greally JM. Retargeting of macroH2A following mitosis to cytogenetic-scale heterochromatic domains. J Cell Biol. 2019 Jun 3;218(6):1810-1823. doi: 10.1083/jcb.201811109. Epub 2019 May 20. PMID: 31110057; PMCID: PMC6548134.</p>
<p>Kong Y, Berko ER, Marcketta A, Maqbool SB, Simões-Pires CA, Kronn DF, Ye KQ, Suzuki M, Auton A, Greally JM. Detecting, quantifying, and discriminating the mechanism of mosaic chromosomal aneuploidies using MAD-seq. Genome Res. 2018 Jul;28(7):1039-1052. doi: 10.1101/gr.226282.117. Epub 2018 May 17. PMID: 29773658; PMCID: PMC6028128.</p>
<p>Lappalainen T, Greally JM. Associating cellular epigenetic models with human phenotypes. Nat Rev Genet. 2017 Jul;18(7):441-451. doi: 10.1038/nrg.2017.32. Epub 2017 May 30. PMID: 28555657. </p>

<p>John M. Greally, DMed, PhD, MB, BCh, BAO, is Chief of the Division of Genomics in the Department of Genetics, Director of the Center for Epigenomics and Professor of Genetics and Pediatrics at Montefiore Einstein. Dr. Greally is a specialist in clinical genetics, with an emphasis on rare diseases and congenital conditions. He has expertise in medical genomics, the use of advanced genomic technologies to diagnose genetic conditions.</p><p>Dr. Greally obtained his Bachelor&rsquo;s degree in Medicine, Surgery and Obstetrics in 1988 from the National University of Ireland in Galway, Ireland. He received his Doctorate of Philosophy in 1999 and his Doctorate of Medicine in 2016 from the same institution.</p><p>Building on his clinical focus, Dr. Greally runs a research program that uses genomic technologies, advanced data analysis techniques and stem cell systems to understand the mechanisms of human genetic diseases, with a focus on rare DNA sequence variants in the non-coding majority of the human genome. He is focused on improving our ability to diagnose rare diseases and on the equitable provision of genomics services to populations of all ancestries. He has also initiated a startup business, Latent Genomics, to allow the effective use of medical genomics in clinical care.</p><p>Dr. Greally holds a United States Patent titled <em>Methods for determining cytosine methylation in DNA and uses thereof</em>. His work has been published in numerous peer-reviewed journals, chapters and books, and he has presented nationally and internationally. He sits on the editorial board of <em>Epigenetics and Chromatin</em> (BioMed Central) and is a section editor for Epigenetics at <em>PLOS Genetics</em>.</p><p>Dr. Greally is board certified in pediatrics by the American Board of Pediatrics and in clinical genetics and genomics by the American Board of Medical Genetics. He is a member of the American Society of Human Genetics and a fellow of the American College of Medical Genetics and Genomics. Dr. Greally has been appointed president of the New York Celtic Medical Society from 2021 to 2023, and in 2014 he won Mentor of the Year in Basic Science from Montefiore Einstein.</p>