TuckerLab @
Our Research
We take a multidisciplinary, collaborative approach to our research, always driven by the ultimate goal of improving human health. The guiding principle is to do the right experiment for the right problem, bringing a "figure it out" spirit to all of our research endeavors. This often leads us into unexpected and difficult territory, which we believe is precisely where transformative discoveries may be found.
High resolution molecular profiling
Advances in molecular biology and sequencing technologies have been a gamechanger for the granularity of our molecular analyses. While whole genome sequencing and bulk RNAseq have become entirely routine, we venture into the next generation of technologies analyzing genetic variation, transcript usage, genome regulation, and protein abundance in a cell-by-cell manner. Our long term focus in cardiology have led to our specialized approaches in these challenging tissues. In the near term, we continue to examine relationships between single cell variation in molecular readouts and phenotype and genetics in model systems and humans. At the same time we continue advancing our laboratory and analysis approaches as the field matures, more recently integrating protein profiling and long-read RNA sequencing.
​
Key publications include:
Tucker NR, Chaffin M, Fleming SJ, Hall AW, Parsons VA, Bedi KC Jr, Akkad A-D, Herndon CN, Arduini A, Papangeli I, Roselli C, Aguet F, Choi SH, Ardlie KG, Babadi M, Margulies KB, Stegmann CM, Ellinor PT. Transcriptional and cellular diversity of the human heart. Circulation. 2020;142:466–482.
Chaffin M, Papangeli I, Simonson B, Akkad A-D, Hill MC, Arduini A, Fleming SJ, Melanson M, Hayat S, Kost-Alimova M, Atwa O, Ye J, Bedi KC Jr, Nahrendorf M, Kaushik VK, Stegmann CM, Margulies KB, Tucker NR, Ellinor PT. Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy. Nature. 2022;608:174–180.
​
Amancherla K, Qin J, Hulke ML, Pfeiffer RD, Agrawal V, Sheng Q, Xu Y, Schlendorf KH, Lindenfeld J, Shah RV, Freedman JE, Tucker NR, Moslehi J. Single-nuclear RNA sequencing of endomyocardial biopsies identifies persistence of donor-recipient chimerism with distinct signatures in severe cardiac allograft vasculopathy. Circ Heart Fail. 2023;16:e010119.
From Variants to Mechanisms for Cardiology and beyond
In the past several decades, the rate of discovery for genetic signatures of traits and diseases has accelerated at breakneck speeds. While this has enabled population scale analyses of genetic associations, it has also left us with a mechanistic gap in how these signatures relate to their trait. Just recently have we begun to see successful translation of limited targets into clinical therapeutics or actionable risk stratification, but the potential remains vast. Our goal is to unlock these genetic signatures under the belief that each represents a unique biological mechanism which may ultimately be translationally actionable. To accomplish this, we incorporate multi-disciplinary approaches spanning functional genomics, advanced genetic editing, and studies of cellular and model organism physiology.
​
Key Publications:
Jameson HS, Hanley A, Hill MC, Xiao L, Ye J, Bapat A, Ronzier E, Hall AW, Hucker WJ, Clauss S, Barazza M, Silber E, Mina JA, Tucker NR, Mills RW, Dong J-T, Milan DJ, Ellinor PT. Loss of the atrial fibrillation-related gene, Zfhx3, results in atrial dilation and arrhythmias. Circ Res. 2023;133:313–329.
​Hall AW, Chaffin M, Roselli C, Lin H, Lubitz SA, Bianchi V, Geeven G, Bedi K, Margulies KB, de Laat W, Tucker NR, Ellinor PT. Epigenetic analyses of human left atrial tissue identifies gene networks underlying atrial fibrillation. Circ Genom Precis Med. 2020;13:e003085.
​
Tucker NR, Dolmatova EV, Lin H, Cooper RR, Ye J, Hucker WJ, Jameson HS, Parsons VA, Weng L-C, Mills RW, Sinner MF, Imakaev M, Leyton-Mange J, Vlahakes G, Benjamin EJ, Lunetta KL, Lubitz SA, Mirny L, Milan DJ, Ellinor PT. Diminished PRRX1 expression is associated with increased risk of atrial fibrillation and shortening of the cardiac action potential. Circ Cardiovasc Genet . 2017;10.
Identifying the mechanisms of evolved solutions to human cardiovascular disease from across the animal kingdom
We have studied human physiological and genetic diversity extensively, unraveling key biological pathways with hopes of developing the next life-saving therapeutic. While much of this effort is picking through miniscule effect sizes and multifactorial, highly confounded datasets, one group of subjects has always been of particular interest: those with physiological extremes of both health and disease. While the studies of these human populations continue, we ask: Why limit ourselves to the diversity of humankind, when the animal kingdom may offer solutions to cardiovascular problems that plague our species?
As examples, grizzly bears experience cardiac stiffness in hibernation which resolves upon waking. Such a condition is essentially irreversible in humans. Alternatively, giraffes often experience blood pressures that would be a medical crisis in humans, yet experience none of the maladaptive remodeling we see in our species.
​
To further this bio-inspired approach, we use the advanced molecular approaches described above, and together with the expertise of our collaborators ranging from comparative physiologists, veterinarians, comparative genomicists, and biomedical engineers, we work to unlock the secrets of these amazing evolved solutions to the cardiovascular maladies of humankind.
Key publications:
Armstrong EE, Perry BW, Huang Y, Garimella KV, Jansen HT, Robbins CT, Tucker NR, Kelley JL. A beary good genome: Haplotype-resolved, chromosome-level assembly of the brown bear (Ursus arctos). Genome Biol Evol. 2022;14.
​
Eaton DM, Berretta RM, Lynch JE, Travers JG, Pfeiffer RD, Hulke ML, Zhao H, Hobby ARH, Schena G, Johnson JP, Wallner M, Lau E, Lam MPY, Woulfe KC, Tucker NR, McKinsey TA, Wolfson MR, Houser SR. Sex-specific responses to slow progressive pressure overload in a large animal model of HFpEF. Am J Physiol Heart Circ Physiol. 2022;323:H797–H817.