Michael Alexanian, PhD
Heart disease is a global epidemic and accounts for 1 in every 5 deaths in the US. In many human diseases, stress-activated signalling cascades alter chromatin, triggering changes in gene expression that fuel progressive organ dysfunction. Our team studies how chromatin receives, processes, and amplifies environmental stress signals that drive changes in cell states leading to heart disease.
Alexanian’s group leverage a host of specialized tools and techniques including single-cell genomic, whole organ in vivo physiology, murine genetic models, CRISPR screens and computational biology. Most recently, our research revealed the mechanism underlying the beneficial effect of small molecule bromodomain inhibitors in heart failure, demonstrating that rather than affecting cardiomyocytes, the drugs control the activation of fibroblasts, with direct impact on cardiac function. This work has revealed novel molecular mechanisms critical for controlling cardiac fibrosis, including the identification of the transcription factor MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction. In ongoing work, our group has developed a research program that delves into heart failure pathogenesis from a cell-cell communication perspective, with the goal of identifying signaling molecules that control cross-talk between stromal, muscle, immune and vascular cells. Refinement of the molecular mechanisms controlling such crosstalk may inform new therapeutic strategies for a wide variety of chronic disorders that feature maladaptive remodelling of cell state and tissue architecture.
Our long-term aspirational goal is to contribute to the understanding of how to target gene regulation in a cell specific manner to treat human disease.
The major research goals of our laboratory are:
- Uncover the molecular mechanisms governing dynamic changes in cell states in cardiovascular disease
- Define the crosstalk between stromal, muscle, immune and vascular cells in cardiovascular disease
- Develop approaches to therapeutically target maladaptive cell states in diseases that feature pathological remodeling of tissue architecture such as heart failure
Featured Publications
Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis
Michael Alexanian#, Arun Padmanabhan, Tomohiro Nishino, Joshua G. Travers, Lin Ye, Clara Youngna Lee, Nandhini Sadagopan, Yu Huang, Angelo Pelonero, Kirsten Auclair, Ada Zhu, Barbara Gonzalez Teran, Will Flanigan, Charis Kee-Seon Kim, Koya Lumbao-Conradson, Mauro Costa, Rajan Jain, Israel Charo, Saptarsi M. Haldar, Katherine S. Pollard, Ronald J. Vagnozzi, Timothy A. McKinsey, Pawel F. Przytycki, Deepak Srivastava
#Denotes corresponding author
bioRxiv, 2022
Transcriptional plasticity of fibroblasts in heart disease
Rudi Micheletti and Michael Alexanian#
#Denotes corresponding author
Biochemical Society Transactions, 2022
A Transcriptional Switch Governs Fibroblast Activation in Heart Disease
Michael Alexanian, Pawel F Przytycki, Rudi Micheletti, Arun Padmanabhan, Lin Ye, Joshua G Travers, Barbara Gonzalez Teran, Qiming Duan, Sanjeev S Ranade, Franco Felix, Ricardo Linares-Saldana, Yu Huang, Gaia Andreoletti, Jin Yang, Kathryn N Ivey, Rajan Jain, Timothy A McKinsey, Michael G Rosenfeld, Casey Gifford, Katherine S Pollard, Saptarsi M Haldar, Deepak Srivastava
Nature, 2021=
BRD4 (Bromodomain-Containing Protein 4) Interacts with GATA4 (GATA Binding Protein 4) to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes
Arun Padmanabhan#, Michael Alexanian#, Ricardo Linares-Saldana#, Bárbara González-Terán, Gaia Andreoletti, Yu Huang, Andrew J Connolly, Wonho Kim, Austin Hsu, Qiming Duan, Sarah AB Winchester, Franco Felix, Juan A Perez-Bermejo, Qiaohong Wang, Li Li, Parisha P Shah, Saptarsi M Haldar, Rajan Jain, Deepak Srivastava
#Denotes shared co-first authorship
Circulation, 2020
A transcribed enhancer dictates mesendoderm specification in pluripotency
Michael Alexanian, Daniel Maric, Stephen P Jenkinson, Marco Mina, Clayton E Friedman, Ching-Chia Ting, Rudi Micheletti, Isabelle Plaisance, Mohamed Nemir, Damien Maison, Jasmin Kernen, Iole Pezzuto, Dominic Villeneuve, Frédéric Burdet, Mark Ibberson, Stephen L Leib, Nathan J Palpant, Nouria Hernandez, Samir Ounzain, Thierry Pedrazzini
Nature communications, 2017