Integrated Large-Scale, Single-Cell Transcriptomic and Epigenomic Profiling to Understand Cardiomyopathy
Abstract
Project Overview: A fundamental challenge in understanding cardiomyopathy is that there are many different cell types in the heart, each with substantial functional heterogeneity. These cardiac cells undergo cell type-specific remodeling during the development of cardiomyopathy, including substantial modifications in their nuclear transcriptome (gene expression) and epigenome (modifications of DNA and associated proteins). These cell type-specific transcriptome and epigenome remodeling drive functional changes underlying the pathophysiology of cardiomyopathy. However, such cell type-specific transcriptome and epigenome changes remain little understood. Here we propose to use the latest state-of-the-art single-nucleus RNA sequencing (snRNA-Seq) or Assay for Transposase-Accessible Chromatin using sequencing (snATAC-Seq) technologies to comprehensively investigate how cell type-specific transcriptome and epigenome remodeling occur along the progression of cardiomyopathy. Statement of Problem: Cardiomyopathy, the cardiac muscle-related disease, is characterized by decreased cardiac function. Cardiomyopathy often leads to heart failure (HF), arrhythmia, and even sudden cardiac death. These cardiac diseases affect millions of people and result in ~$40 billion in healthcare cost every year in the U.S. Current available treatment options for cardiomyopathy and HF are mostly for symptom relief and many patients eventually require a heart transplant. This is at least partly due to our incomplete understanding of their pathophysiology. Cardiomyopathy is among the Peer Reviewed Medical Research Program Topic Areas and affects tens of thousands of military Service members, Veterans, their dependents as well as the general public. A fundamental challenge in understanding cardiomyopathy is that there are many different cell types in the heart, each with substantial functional heterogeneity. These cardiac cells undergo cell type-specific remodeling during the development of cardiomyopathy and HF, including substantial modifications in their transcriptional and epigenetic states that drive functional changes underlying the pathophysiology of cardiomyopathy and HF. Therefore, a fundamental question and a significant knowledge gap in cardiomyopathy is how exactly different cardiac cells types remodel their transcriptome and epigenome. Innovation: Our studies proposed herein contain both conceptual and technological innovations: • We will reveal, for the first time to our knowledge, comprehensive genome-wide transcriptional and epigenetic changes in a widely used mouse model of cardiomyopathy, using state-of-the-art large-scale snRNA-Seq and snATAC-Seq methods. • We are using and developing advanced bioinformatics tools for integrated single-cell/nucleus transcriptome and epigenome analysis. This will uncover the transcription regulators that open the chromatin and impact gene expression, thereby providing novel insights into how cardiomyopathy-initiating factors such as hypertension is transmitted to downstream nuclear transcriptional and epigenetic changes. • Combining all these innovations together, our integrated, large-scale, single-cell transcriptomic and epigenomic analysis approach will help answer a fundamental question in cardiomyopathy, that is how cell type-specific transcriptomic and epigenomic remodeling occur during the development of cardiomyopathy. Impact: We believe that our proposed studies will generate significant scientific and clinical impact: • Our innovative single-nucleus transcriptome and epigenome approaches and integrated data analysis methods will significantly advance our understanding of cardiomyopathy and be generally applicable to many other areas of biology including cardiovascular disease which is the #1 killer in the U.S. • Our proposed studies will bring novel insights into a fundamental question in cardiomyopathy: how cell type-specific transcriptomic and epigenomic remodelin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010089
Entities
People
- Liming Pei
Organizations
- United States Army