Yang Zhou, Ph.D., assistant professor in the Department of Biomedical Engineering, has received a new NIH R01 grant to study ELMSAN1, a protein that regulates gene activity in heart cells and could potentially help protect the heart from disease.
The four-year award launches a new research direction for the Zhou Lab, which already studies cardiac cell reprogramming and regeneration. Together, the two research programs investigate how gene regulatory mechanisms establish, maintain, and potentially restore cardiac cell identity and function.
“This award is an exciting milestone for our lab and supports a new research direction focused on understanding how the heart maintains its function and responds to disease,” said Zhou.
A cross-campus effort
The project is bringing together investigators from four UAB departments, each contributing complementary expertise to address key questions in cardiovascular biology.
Zhou’s co-investigators include Jianyi (Jay) Zhang, Ph.D., distinguished professor and chair of the Department of Biomedical Engineering; Adam Wende, Ph.D., professor in the Department of Pathology’s Division of Molecular and Cellular Pathology; Rui Lu, Ph.D., associate professor in the Department of Medicine’s Division of Hematology and Oncology; and Yanfeng Zhang, Ph.D., assistant professor in the Department of Genetics.
Drawing on engineering, pathology, medicine, and genetics, the team will trace how ELMSAN1 shapes gene activity in heart cells, from the molecular level to the whole heart.
The protein sustaining the pulse
Behind every heartbeat is a carefully timed system of genes switching on and off inside heart cells. When that system falls out of sync, the heart can lose its ability to produce energy, pump effectively, and withstand stress.
“Our heart cells rely on precise control of gene activity to function properly and adapt to stress,” said Zhou. “We study a protein called ELMSAN1, which is a noncatalytic component of a histone deacetylase (HDAC) complex that helps regulate gene activity.”
Building on earlier research showing that ELMSAN1 is essential for normal heart function, Zhou’s team will now examine how the protein controls gene activity and whether it also protects the heart from pathological stress, a harmful strain that can lead to heart failure.
Early evidence of an essential protein
The Zhou Lab was among the first to investigate ELMSAN1 in heart cells. In two published studies using human stem cell-derived heart muscle cells and genetically engineered mice, the team showed that losing ELMSAN1 disrupted core functions such as energy metabolism and contraction, eventually leading to heart failure in the mice.
“More recently, our preliminary studies suggest that ELMSAN1 deficiency also makes the heart more vulnerable to pathological stress,” said Zhou. “These findings are particularly exciting because they reveal an important role for a previously overlooked component of a gene-regulating protein complex, opening new opportunities to understand how these complexes function in heart disease.”
By identifying ELMSAN1 as a key player in keeping the heart healthy, these early discoveries are shaping the next chapter of Zhou’s research.
Testing the heart’s tipping point
In the next phase, the team will take a closer look at how ELMSAN1 works at the molecular level and what happens when the heart is pushed beyond its normal workload, a condition called pressure overload that commonly results from high blood pressure.
“Our preliminary findings suggest that loss of ELMSAN1 accelerates cardiac deterioration under pressure overload,” said Zhou. “We now want to determine how ELMSAN1 influences the heart’s response to pathological stress and whether it plays a direct protective role against heart failure.”
What the team learns could reveal whether strengthening ELMSAN1’s role could one day help the heart hold its ground against disease.
Future precision for patients
Drugs that target epigenetic enzymes, which help control gene activity, have shown promise in cardiovascular research. But making those drugs specific enough to avoid unwanted effects remains a major hurdle.
“While most studies have focused on the HDAC enzymes themselves, our research takes a different perspective by investigating their noncatalytic regulatory partners, such as ELMSAN1, which may help determine how these complexes function in specific biological contexts,” said Zhou. “Although our current work focuses on understanding the underlying mechanisms and testing their roles in experimental models, we hope these discoveries will provide a foundation for developing more precise strategies to preserve heart function and prevent or slow heart failure.”
By uncovering how an understudied protein helps heart cells hold steady under stress, Zhou and her collaborators hope to lay the groundwork for therapies that protect the heart with greater precision, offering new possibilities for the millions of people living with or at risk of heart failure.