Positions

Assistant Professor
Molecular and Human Genetics
Baylor College of Medicine
Houston, TX, US

Education

MD from Peking University Health Science Center
PhD from Johns Hopkins University
Human Genetics and Molecular Biology
Postdoctoral Fellowship at Johns Hopkins University
Internship at University Hospitals Case Medical Center
Internal Medicine
Residency at University Hospitals Case Medical Center
Internal Medicine
Fellowship at University Hospital Case Medical Center
Medical Genetics
Postdoctoral Fellowship at Case Western Reserve University

Certifications

Texas Medical Board
Ohio Medical Board
American Board of Medical Genetics and Genomics
American Board of Internal Medicine

Professional Interests

  • Genetic and Epigenetic regulation of heart failure and cardiomyopathies

Professional Statement

The overarching theme of our laboratory is to understand the genomic and epigenomic regulation of the cardiovascular system in health and in disease with an emphasis on heart failure and cardiomyopathies.

Heart failure has been associated with a stereotypical gene expression program controlled by a series of transacting factors and chromatin state changes and is a result of a series of maladaptive remodeling of the myocardium. The aberrant activation of key transcription factors such as MEF2, NFAT, NF-κB, GATA4, and C-MYC have been shown to play critical roles in this program switching. However, the precise molecular mechanisms that signal these transcription factors and trigger pathologic gene expression in the heart remain poorly understood and thus an effective way to counter act is unavailable. Current state-of-the-art therapy aims to reduce the neurohormonal stress and improves hemodynamics, however, the already committed gene program cannot be reversed.

REV-ERBα is a nuclear receptor and transcriptional repressor in the automatic core clock machinery. We have discovered that REV-ERBα colocalizes with aberrantly activated key transcription factors, prevents activation of their targets and protects the myocardium from pathological remodeling in vitro and in vivo in both neurohormonal and hemodynamics stress models. This finding led to a drastically different model from the currently held hypothesis, instead we propose the aberrant gene expression program is the cause rather than the result of pathological remodeling. Also, the widely accepted early phase “adaptive” remodeling is not required to preserve normal cardiac function and actually may contribute to the pathological switch of gene expression program. This finding also offers a pathway for the development of novel therapies for heart failure.

Another focus of our laboratory is to study patient-derived induced pluripotent stem cell differentiated cardiomyocytes from patients with inherited cardiomyopathies. Using a comprehensive panel of phenotyping tools (biophysics, electrophysiology, energetics, and imaging) combined with genomics tools, we aim to establish a platform to diagnose the molecular defects, characterize the pathogenic pathways and develop targeted therapy.

Our laboratory is also interested in understanding the genomic and epigenomic regulation of the adaptive gene regulatory programs in the cardiovascular system, such as circadian rhythm, exercise and fasting. Using RNAseq, we are the first to demonstrate that there is a temporal and functional organization of oscillating transcripts, with a distinct energy-regulatory phase (coinciding with active phase) and a remodeling and repair phase (coinciding with resting phase) in a 24-hour period. We identified that a local transcription factor KLF15 governs 75% of the oscillating transcripts and establishes this bimodal landscape by both directly activating catabolic targets during the active phase and repressing aberrant oscillation via recruiting circadian repressor REV-ERBα and its cofactor NCOR. These findings demonstrated a novel molecular mechanistic principle of “positive” and “negative” regulation in circadian gene regulation and provided a framework to explain the longstanding observation that the same molecular clock gives rise to different sets of oscillating genes in different tissues.

Selected Publications