Michael Alexanian, PhD

Assistant Investigator
Assistant Professor
Gladstone Institutes
Department of Pediatrics
[email protected]
[email protected]
Research Overview: 

Heart disease is a global epidemic, responsible for 1 in every 5 deaths in the U.S. In many diseases, stress-activated signaling pathways trigger chromatin rewiring, activating pathological gene expression that contributes to progressive organ dysfunction. Our lab explores how chromatin receives, processes, and amplifies stress signals that drive changes in cell states, leading to inflammatory and fibrotic diseases, such as heart failure. The Alexanian lab uses a variety of specialized tools and techniques, including single-cell genomics, whole-organ in vivo physiology, stem cells, murine genetic models, CRISPR screens, and computational biology. Our recent research has uncovered the mechanism behind the beneficial effects of small-molecule bromodomain inhibitors in heart failure. We found that these drugs do not directly affect cardiomyocytes, but instead regulate fibroblast and macrophage activation, ultimately impacting cardiac function. These studies have revealed novel molecular pathways critical for controlling stress-induced fibroblast activation and the crosstalk between inflammation and fibrosis. 

Our ongoing research delves into the pathogenesis of heart failure from a cell-cell communication perspective. We aim to identify signaling molecules that control interactions between stromal, muscle, immune, and vascular cells. Understanding the molecular mechanisms behind this crosstalk will open up new therapeutic avenues for chronic diseases characterized by maladaptive tissue remodeling, such as heart failure. Ultimately, our goal is to contribute to the development of targeted therapies that can modulate gene regulation in a cell-specific manner to treat human diseases. The major research goals of our laboratory are: 

  1. Investigate the molecular mechanisms driving dynamic changes in cell states during cardiovascular disease. 

  1. Define the crosstalk between stromal, muscle, immune, and vascular cells in cardiovascular disease. 

  1. Develop strategies to therapeutically target maladaptive cell states in diseases with pathological tissue remodeling, 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

Primary Thematic Area: 
Vascular & Cardiac Biology
Secondary Thematic Area: 
Developmental & Stem Cell Biology
Research Summary: 
Our team studies how chromatin receives, processes, and amplifies environmental stress signals that drive changes in cell states leading to heart disease.

Websites

Publications: 

BRD4 inhibition rewires cardiac macrophages toward a protective phenotype marked by low MHC class II expression.

American journal of physiology. Heart and circulatory physiology

Schuetze KB, Stratton MS, Bagchi RA, Hobby ARH, Felisbino MB, Rubino M, Toni LS, Reges C, Cavasin MA, McMahan RH, Alexanian M, Vagnozzi RJ, McKinsey TA

Chromatin remodelling drives immune cell-fibroblast communication in heart failure.

Nature

Alexanian M, Padmanabhan A, Nishino T, Travers JG, Ye L, Pelonero A, Lee CY, Sadagopan N, Huang Y, Auclair K, Zhu A, An Y, Ekstrand CA, Martinez C, Teran BG, Flanigan WR, Kim CK, Lumbao-Conradson K, Gardner Z, Li L, Costa MW, Jain R, Charo I, Combes AJ, Haldar SM, Pollard KS, Vagnozzi RJ, McKinsey TA, Przytycki PF, Srivastava D

A genome-wide CRISPR screen identifies BRD4 as a regulator of cardiomyocyte differentiation.

Nature cardiovascular research

Padmanabhan A, de Soysa TY, Pelonero A, Sapp V, Shah PP, Wang Q, Li L, Lee CY, Sadagopan N, Nishino T, Ye L, Yang R, Karnay A, Poleshko A, Bolar N, Linares-Saldana R, Ranade SS, Alexanian M, Morton SU, Jain M, Haldar SM, Srivastava D, Jain R

Single Cell Multimodal Analyses Reveal Epigenomic and Transcriptomic Basis for Birth Defects in Maternal Diabetes.

Nature cardiovascular research

Nishino T, Ranade SS, Pelonero A, van Soldt BJ, Ye L, Alexanian M, Koback F, Huang Y, Sadagopan N, Lam A, Zholudeva LV, Li F, Padmanabhan A, Thomas R, van Bemmel JG, Gifford CA, Costa MW, Srivastava D

Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis.

bioRxiv : the preprint server for biology

Alexanian M, Padmanabhan A, Nishino T, Travers JG, Ye L, Lee CY, Sadagopan N, Huang Y, Pelonero A, Auclair K, Zhu A, Gonzalez Teran B, Flanigan W, Kim CK, Lumbao-Conradson K, Costa M, Jain R, Charo I, Haldar SM, Pollard KS, Vagnozzi RJ, McKinsey TA, Przytycki PF, Srivastava D