Our Research
Fetal heart cells are small, still able to divide, and rely heavily on glycolysis. Before and after birth, that changes: they withdraw from the cell cycle, assemble mature contractile machinery, and transition toward mitochondrial oxidative metabolism. Few cells in the body remodel themselves so completely, and the window in which this happens is narrow. When the process goes wrong, it can contribute to congenital heart disease, cardiomyopathy, and heart failure. We study the regulatory layers that coordinate this transformation—chemical marks on RNA, signals from nerves, and switches in the noncoding genome. By working with mouse models alongside human stem cell-derived cardiomyocytes, we can test discoveries across complementary systems.
Epitranscriptomic Control of Heart Development
Messenger RNAs carry chemical modifications that are not encoded in the genome. The most abundant internal modification, m6A, can influence how a transcript is processed, how long it survives, and how efficiently it is translated—adding a layer of regulation after a gene is switched on. The developing heart provides a powerful setting in which to study this control. As cardiomyocytes mature, they progressively increase their reliance on mitochondrial oxidative metabolism, a transition that must occur on schedule for normal heart development. Our recent work shows that m6A is required for this process: without METTL14, a core component of the m6A methyltransferase complex, cardiomyocytes fail to assemble a functional respiratory chain and the heart does not develop normally (Lei et al., bioRxiv, 2026). We use nanopore sequencing to measure methylation on individual RNA molecules and targeted RNA editing to install m6A at defined positions in human cardiomyocytes. These approaches allow us to ask not only whether m6A matters, but how its amount and position shape RNA fate, protein production, and cardiac development.
The Neuron-Heart Axis
Sympathetic nerves innervate the heart during development, and they do more than regulate heart rate—they help coordinate how the heart grows and matures. We generated sympathetic neurons from human pluripotent stem cells and showed that they form functional connections with cardiomyocytes (Cell Stem Cell, 2016). In mice, we found that sympathetic neurons regulate cardiomyocyte proliferation through the circadian clock genes Per1 and Per2, revealing an unexpected link between neural activity and the cardiomyocyte cell cycle (Science Advances, 2021). This communication is bidirectional. Together with our collaborators, we have shown how glia and signals from target tissues shape sympathetic-neuron development and function (eLife, 2022; Cell Reports, 2024, 2025). We are now investigating how neural input helps determine the timing of cardiomyocyte cell-cycle exit and maturation—and how disrupting that input alters heart development and function.
Enhancers of Heart Development and Disease
Most genetic variants linked to heart-failure risk do not alter proteins. Instead, they lie in noncoding regions of the genome that control when, where, and how strongly genes are expressed. These regions include enhancers—molecular switches that can regulate genes across long genomic distances. Working with genetic epidemiologists, we implicated ACTN2 in heart-failure risk (Nature Communications, 2020) and then identified a conserved enhancer located far from the gene itself. Deleting this single switch in human iPSC-derived cardiomyocytes and in mice prevents cardiomyocytes from fully maturing, affecting their structure, function, and metabolism through the HSP90AA1–mTOR axis (Nature Cardiovascular Research, 2024). We are now mapping the noncoding elements that guide cardiomyocyte maturation and asking how variants within these elements predispose people to cardiomyopathy.
Turning "on and off" cardiomyocyte contraction
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