Project Summary
Heart failure (HF) has a high morbidity and mortality. Its incidence is increasing worldwide. One hallmark of
HF is endothelial cell (EC) dysfunction which initially manifests as impaired endothelium-dependent
vasodilation of the epicardial coronary arteries and the microvasculature. Another important hallmark of HF is
the presence of interstitial fibrosis, which increases myocardial stiffness and cardiac work, elevates diastolic
pressures and increases pulmonary interstitial fluid to impair oxygenation. Genetic lineage tracing showed that
most HF fibroblasts originate from tissue-resident fibroblasts, which expand and differentiate into
myofibroblasts. However, the molecular mechanisms regulating fibroblast activation and myofibroblast
transdifferentiation remain poorly understood. Intercellular communication, especially EC-fibroblast crosstalk,
plays a substantial modulatory role in the normal and failing heart. More specifically, factors secreted by
cardiac microvascular EC modulate cardiac performance and cardiac fibrosis. Thus, targeting endothelial
dysfunction has the potential to be a promising therapeutic avenue for HF.
Recently, we and other groups discovered that genes important for the control of cell identity exhibit a
unique epigenetic signature, e.g., broad enrichment of the activating histone modification H3K4me3 and super-
enhancer marks. These discoveries prompted our pilot work to develop the first computational model for the
discovery of new EC master regulators. This novel model employs an analysis of both the epigenetic
landscape as well as the gene expression network. It successfully recaptured known EC identity genes with
high sensitivity and accuracy. The model further revealed a number of top ranked genes with no reported role
in EC, making them promising candidates as novel EC identity genes. One of the most top-ranked genes is
transcription factor 4 (TCF4), which displays typical features of cell identity gene in EC.
Interestingly, we have preliminary data showing that TCF4 function is a master regulator that maintains EC
identity. Further, TCF4 is downregulated in cardiac ECs of HF patients compared to non-failing controls. The
silencing of TCF4 in EC leads to an increase of EC-secreted proteins TGFß1, which stimulate fibroblast
activation and myofibroblasts transdifferentiation, and thus promote cardiac fibrosis. In this proposal, we will
investigate the role of TCF4 in EC identity maintenance. We will further investigate the role of TCF4 in the
crosstalk between ECs and fibroblasts, and reveal TCF4 as a therapy target to prevent cardiac fibrosis in HF.
Successful completion of this proposal will be the first to define TCF4 as a novel EC master regulator that
maintains EC phenotype and function. We will uncover an overlooked determinant of HF -- loss of EC identity.
TCF4 dysregulation disturbs EC-fibroblast crosstalk within the heart, aggravating cardiac fibrosis in HF.
Therapeutic modulation of EC-specific TCF4 delivery may be a novel and promising approach for treating HF.