Areas of Investigation
Many cardiovascular diseases and traits have a strong heritable component, yet the mechanisms through which this genetic variation acts remain unknown. Our lab aims identify these mechanisms for variants of both large and small effect sizes (familial and population scale genetics, respectively). To accomplish this, we utilize a variety of technical and analytic approaches, including large-scale genetic screening, low input ‘omics, functional genomics and animal modeling. Two overarching themes for our research are:
- Variants to function in cardiovascular disease. Genome wide association studies (GWAS) have identified thousands of regions in the human genome that associate with disease. However, linking these regions to the relevant gene, identifying the transcriptional effect of that variation, and understanding how this affects phenotype has been the great challenge for truly leveraging the genetic data for understanding of disease biology. We tackle these problems at each regulatory level, performing assays to identify active and inactive chromatin, examining the 3D conformation of these regions both directly and indirectly, and modeling perturbed gene outputs both in vitro and in vivo.
- Using low input ‘omics to identify signatures for health and disease. Recent advances in single cell transcriptomics have allowed us to profile transcriptomes of cell types and subtypes to a resolution not previously possible. We have recently used these approaches to profile the signatures found in the adult non-failing heart (see figure). We continue to apply these and orthogonal approaches (such as single cell ATAC) to discover differences between cell types in both human samples and those derived from animal models of health and disease. By generating these data and intersecting them with genetic studies, we hope to better define target genes and pathways for potential therapeutic intervention. Importantly, these approaches are rapidly evolving making this an exciting area of development both technically and analytically for our group.
- Functional genomics
- Low-input transcriptomics and epigenomics
- Large-scale variant screening
- Modeling of variant function (cells, organoids and model organisms)
Assistant Professor, Masonic Medical Research Institute
Dr. Tucker joined the faculty of the MMRI in March 2020 to lead efforts to understanding the genetic basis of cardiovascular disease risk. Prior to the present appointment, Dr. Tucker served as a project team lead in the Precision Cardiology Laboratory at the Broad Institute of MIT and Harvard, a joint effort between the Broad Institute and Bayer to identify novel mechanisms and potential therapeutic targets for cardiovascular disease. While there, he led efforts to employ low input transcriptomic and epigenomic approaches in human and model system cardiovascular tissues. He also served as an Instructor of Medicine at Massachusetts General Hospital and Harvard Medical School. Prior to joining the Broad Institute in 2016, he served as a postdoctoral research fellow at Massachusetts General Hospital where he focused on the genetic underpinnings of common and rare variant driven atrial fibrillation, mitral valve prolapse, and cardiomyopathies in the laboratory of Patrick Ellinor. Nathan holds a Ph.D in cell biology and genetics from Washington State University and a B.S in biology from Syracuse University.
Assistant Professor, Masonic Medical Research Institute
BS Biology, Syracuse University, 2004
PhD Cell Biology and Genetics, Washington State University, 2011
NIH K01HL140187, PI: Nathan Tucker, DEFINING THE FUNCTIONAL VARIATION UNDERLYING ATRIAL FIBRILLATION RISK, 07/15/2018-05/31/2023
Research Associate/Genetics Core Co-Manager
Ryan Pfeiffer joined the MMRI in 2003 as a research assistant in the laboratory of Dr. Ramon Brugada in the Molecular Genetics department. His main focus has been on the genetic basis of cardiac arrhythmia’s and structural heart disease. In 2006, he played a key role in obtaining CLIA/CLEP laboratory approval for molecular genetic testing in cardiac arrhythmias and establishing a Clinical Genetic Testing Laboratory at the institute. In 2009, Ryan obtained his New York State license in Clinical Laboratory Technology and was promoted to the position of Supervisor of Genetic Screening/ Clinical Laboratory Supervisor. In 2018, he accepted his current position as Genetics Core Manager. Ryan has been pivotal in integrating new equipment and technologies to improve laboratory capabilities and maintain a state-of-the-art laboratory at MMRI. He has been involved in many different cardiac research projects ranging from electrical diseases of the heart to structural heart diseases.
Over the years, Ryan has mentored many undergraduate, graduate, and post-doctoral students as well as visiting scientists from around the world, and co-authored dozens of scientific manuscripts and abstracts. Ryan holds a B.S. in Bioinformatics and Molecular Biology from Rensselaer Polytechnic Institute.
Associate Computational Biologist I
Michelle Hulke joined MMRI and the Tucker lab in August 2020. Michelle recently completed her doctoral studies at Cornell University, where she studied DNA replication timing. Her work focused primarily on the relationship of DNA replication timing with embryo development and the accumulation of germline mutations, as well as the localization of replication origins in the human genome. Originally trained as a molecular biologist, Michelle transitioned into computational biology, where she now works to combine both aspects of genetics in a complementary fashion. Michelle holds a Ph.D. in genetics from Cornell University and a B.A. in biology from Gustavus Adolphus College.
- Tucker, NR, Chaffin, M, Bedi, KC Jr, Papangeli, I, Akkad, AD, Arduini, A et al.. Myocyte-Specific Upregulation of ACE2 in Cardiovascular Disease: Implications for SARS-CoV-2-Mediated Myocarditis. Circulation. 2020;142 (7):708-710. doi: 10.1161/CIRCULATIONAHA.120.047911. PubMed PMID:32795091 PubMed Central PMC7424896.
- van Ouwerkerk, AF, Hall, AW, Kadow, ZA, Lazarevic, S, Reyat, JS, Tucker, NR et al.. Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation. Circ. Res. 2020;127 (1):34-50. doi: 10.1161/CIRCRESAHA.120.316574. PubMed PMID:32717170 .
- Tucker, NR, Chaffin, M, Bedi, KC, Papangeli, I, Akkad, AD, Arduini, A et al.. Myocyte Specific Upregulation of ACE2 in Cardiovascular Disease: Implications for SARS-CoV-2 mediated myocarditis. medRxiv. 2020; :. doi: 10.1101/2020.04.09.20059204. PubMed PMID:32511660 PubMed Central PMC7277016.
- Ntalla, I, Weng, LC, Cartwright, JH, Hall, AW, Sveinbjornsson, G, Tucker, NR et al.. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. Nat Commun. 2020;11 (1):2542. doi: 10.1038/s41467-020-15706-x. PubMed PMID:32439900 PubMed Central PMC7242331.
- Tucker, NR, Chaffin, M, Fleming, SJ, Hall, AW, Parsons, VA, Bedi, KC Jr et al.. Transcriptional and Cellular Diversity of the Human Heart. Circulation. 2020; :. doi: 10.1161/CIRCULATIONAHA.119.045401. PubMed PMID:32403949 .
- van Ouwerkerk, AF, Bosada, FM, Liu, J, Zhang, J, van Duijvenboden, K, Chaffin, M et al.. Identification of Functional Variant Enhancers Associated With Atrial Fibrillation. Circ. Res. 2020;127 (2):229-243. doi: 10.1161/CIRCRESAHA.119.316006. PubMed PMID:32248749 .
- Zhang, M, Hill, MC, Kadow, ZA, Suh, JH, Tucker, NR, Hall, AW et al.. Long-range Pitx2c enhancer-promoter interactions prevent predisposition to atrial fibrillation. Proc. Natl. Acad. Sci. U.S.A. 2019;116 (45):22692-22698. doi: 10.1073/pnas.1907418116. PubMed PMID:31636200 PubMed Central PMC6842642.
- Yu, M, Georges, A, Tucker, NR, Kyryachenko, S, Toomer, K, Schott, JJ et al.. Genome-Wide Association Study-Driven Gene-Set Analyses, Genetic, and Functional Follow-Up Suggest GLIS1 as a Susceptibility Gene for Mitral Valve Prolapse. Circ Genom Precis Med. 2019;12 (5):e002497. doi: 10.1161/CIRCGEN.119.002497. PubMed PMID:31112420 PubMed Central PMC6532425.
- Morley, MP, Wang, X, Hu, R, Brandimarto, J, Tucker, NR, Felix, JF et al.. Cardioprotective Effects of MTSS1 Enhancer Variants. Circulation. 2019;139 (17):2073-2076. doi: 10.1161/CIRCULATIONAHA.118.037939. PubMed PMID:31070942 PubMed Central PMC6510256.
- Choi, SH, Weng, LC, Roselli, C, Lin, H, Haggerty, CM, Shoemaker, MB et al.. Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation. JAMA. 2018;320 (22):2354-2364. doi: 10.1001/jama.2018.18179. PubMed PMID:30535219 PubMed Central PMC6436530.
- Roselli, C, Chaffin, MD, Weng, LC, Aeschbacher, S, Ahlberg, G, Albert, CM et al.. Multi-ethnic genome-wide association study for atrial fibrillation. Nat. Genet. 2018;50 (9):1225-1233. doi: 10.1038/s41588-018-0133-9. PubMed PMID:29892015 PubMed Central PMC6136836.
- Lin, H, van Setten, J, Smith, AV, Bihlmeyer, NA, Warren, HR, Brody, JA et al.. Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. Circ Genom Precis Med. 2018;11 (5):e002037. doi: 10.1161/CIRCGEN.117.002037. PubMed PMID:29748316 PubMed Central PMC5951629.
- Tucker, NR, Ellinor, PT. Response by Ma et al to Letter Regarding Article, "Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy". Circ Genom Precis Med. 2018;11 (4):e002140. doi: 10.1161/CIRCGEN.118.002140. PubMed PMID:29650770 .
- Hu, R, Morley, MP, Brandimarto, J, Tucker, NR, Parsons, VA, Zhao, SD et al.. Genetic Reduction in Left Ventricular Protein Kinase C-α and Adverse Ventricular Remodeling in Human Subjects. Circ Genom Precis Med. 2018;11 (3):e001901. doi: 10.1161/CIRCGEN.117.001901. PubMed PMID:29540468 PubMed Central PMC5858599.
- Tucker, NR, McLellan, MA, Hu, D, Ye, J, Parsons, VA, Mills, RW et al.. Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy. Circ Cardiovasc Genet. 2017;10 (6):. doi: 10.1161/CIRCGENETICS.117.001780. PubMed PMID:29212899 PubMed Central PMC5802346.
- Tucker, NR, Dolmatova, EV, Lin, H, Cooper, RR, Ye, J, Hucker, WJ et al.. Diminished PRRX1 Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential. Circ Cardiovasc Genet. 2017;10 (5):. doi: 10.1161/CIRCGENETICS.117.001902. PubMed PMID:28974514 PubMed Central PMC5679717.
- Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J et al.. Erratum: Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nat. Genet. 2017;49 (8):1286. doi: 10.1038/ng0817-1286c. PubMed PMID:28747752 .
- Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J et al.. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nat. Genet. 2017;49 (6):946-952. doi: 10.1038/ng.3843. PubMed PMID:28416818 PubMed Central PMC5585859.
- Ye, J, Tucker, NR, Weng, LC, Clauss, S, Lubitz, SA, Ellinor, PT et al.. A Functional Variant Associated with Atrial Fibrillation Regulates PITX2c Expression through TFAP2a. Am. J. Hum. Genet. 2016;99 (6):1281-1291. doi: 10.1016/j.ajhg.2016.10.001. PubMed PMID:27866707 PubMed Central PMC5142106.
- Hanley, A, Walsh, KA, Joyce, C, McLellan, MA, Clauss, S, Hagen, A et al.. Mutation of a common amino acid in NKX2.5 results in dilated cardiomyopathy in two large families. BMC Med. Genet. 2016;17 (1):83. doi: 10.1186/s12881-016-0347-6. PubMed PMID:27855642 PubMed Central PMC5114776.
- Kiando, SR, Tucker, NR, Castro-Vega, LJ, Katz, A, D'Escamard, V, Tréard, C et al.. PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance. PLoS Genet. 2016;12 (10):e1006367. doi: 10.1371/journal.pgen.1006367. PubMed PMID:27792790 PubMed Central PMC5085032.
- Tucker, NR, Mahida, S, Ye, J, Abraham, EJ, Mina, JA, Parsons, VA et al.. Gain-of-function mutations in GATA6 lead to atrial fibrillation. Heart Rhythm. 2017;14 (2):284-291. doi: 10.1016/j.hrthm.2016.10.014. PubMed PMID:27756709 .
- Wang, X, Tucker, NR, Rizki, G, Mills, R, Krijger, PH, de Wit, E et al.. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures. Elife. 2016;5 :. doi: 10.7554/eLife.10557. PubMed PMID:27162171 PubMed Central PMC4862755.
- Tucker, NR, Clauss, S, Ellinor, PT. Common variation in atrial fibrillation: navigating the path from genetic association to mechanism. Cardiovasc. Res. 2016;109 (4):493-501. doi: 10.1093/cvr/cvv283. PubMed PMID:26733238 PubMed Central PMC4777911.
- Dina, C, Bouatia-Naji, N, Tucker, N, Delling, FN, Toomer, K, Durst, R et al.. Genetic association analyses highlight biological pathways underlying mitral valve prolapse. Nat. Genet. 2015;47 (10):1206-11. doi: 10.1038/ng.3383. PubMed PMID:26301497 PubMed Central PMC4773907.
- Sinner, MF, Tucker, NR, Lunetta, KL, Ozaki, K, Smith, JG, Trompet, S et al.. Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. Circulation. 2014;130 (15):1225-35. doi: 10.1161/CIRCULATIONAHA.114.009892. PubMed PMID:25124494 PubMed Central PMC4190011.
- Tucker, NR, Ellinor, PT. Emerging directions in the genetics of atrial fibrillation. Circ. Res. 2014;114 (9):1469-82. doi: 10.1161/CIRCRESAHA.114.302225. PubMed PMID:24763465 PubMed Central PMC4040146.
- Macri, V, Mahida, SN, Zhang, ML, Sinner, MF, Dolmatova, EV, Tucker, NR et al.. A novel trafficking-defective HCN4 mutation is associated with early-onset atrial fibrillation. Heart Rhythm. 2014;11 (6):1055-1062. doi: 10.1016/j.hrthm.2014.03.002. PubMed PMID:24607718 PubMed Central PMC4130372.
- Mahida, S, Mills, RW, Tucker, NR, Simonson, B, Macri, V, Lemoine, MD et al.. Overexpression of KCNN3 results in sudden cardiac death. Cardiovasc. Res. 2014;101 (2):326-34. doi: 10.1093/cvr/cvt269. PubMed PMID:24296650 PubMed Central PMC3896252.
- Tucker, NR, Middleton, RC, Le, QP, Shelden, EA. HSF1 is essential for the resistance of zebrafish eye and brain tissues to hypoxia/reperfusion injury. PLoS ONE. 2011;6 (7):e22268. doi: 10.1371/journal.pone.0022268. PubMed PMID:21814572 PubMed Central PMC3141033.