Biology subjects

Chow, C. S. Y.

Publications and source records attributed to Chow, C. S. Y..

6 recordsLinked to original sources

bioRxiv2026

Combinatorial epigenomic patterns define regulatory programs underlying disease heterogeneity

Complex diseases exhibit substantial variation in clinical presentation and outcome despite shared diagnoses. Current genetic models typically represent inherited risk as a single additive liability, obscuring the diverse biological mechanisms through which variants influence disease. Here, we show that disease-associated variants are organized into recurrent regulatory programs that reveal latent disease mechanisms. Using genome-scale epigenomic maps across human tissues and cell states, we identify regulatory programs that partition disease-associated variants without phenotypic or disease-specific priors. Variants assigned to different programs exert distinct biological effects that translate into divergent clinical outcomes. In type 2 diabetes, these programs reveal previously unrecognized disease subtypes with opposing cardiometabolic profiles that stratify future risk of myocardial infarction and non-alcoholic fatty liver disease. Together, our findings establish that inherited disease risk is organized into latent regulatory programs, revealing a fundamental layer of biological heterogeneity underlying complex disease.

genomics↗

bioRxiv2026

Protocol-dependent cardiomyocyte states determine disease modelling capacity of human iPSCs

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are widely used to model cardiovascular disease, yet numerous differentiation protocols generate cardiomyocytes with heterogeneous molecular and functional properties, complicating experimental design. Here we systematically compare sixteen commonly used cardiomyocyte differentiation protocols and characterize their resulting cell states using single-nucleus RNA sequencing, functional phenotyping and computational integration with human genetic data. Despite similar cardiomyocyte yields, protocols produced distinct transcriptional programs, subtype compositions and physiological properties. By integrating protocol-specific gene expression signatures with genome-wide association studies of cardiovascular traits, we identify cardiomyocyte states enriched for genetic architectures underlying specific diseases. These analyses accurately predict protocols most suitable for modelling particular disease contexts, including electrophysiological defects associated with Brugada syndrome and metabolic vulnerability relevant to myocardial infarction. Our results demonstrate that differentiation protocols encode biologically distinct cardiomyocyte states with differential disease relevance and establish a framework for aligning stem-cell differentiation strategies with human complex trait genetics to guide model selection. This approach enables rational design of iPSC-based disease models and highlights how population-scale genetic data can inform experimental systems in stem cell biology.

systems biology↗

bioRxiv2026

Hierarchical control of cardiomyocyte maturation and ischaemia sensitivity by metabolic culture conditions

Ischaemic heart disease remains the leading cause of mortality worldwide, yet no therapies prevent cardiomyocyte death during acute ischaemia-reperfusion injury (IRI). Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a platform for modelling cardiac injury, but their immature phenotype limits the physiological fidelity of in vitro models. Here, we systematically evaluated how experimental variables used during preparation of hiPSC-CM endpoint assays influence cardiomyocyte maturation and susceptibility to IRI. Integrating literature mining, molecular profiling, statistical genetics, and functional assays, we examined the effects of replating conditions, backbone media, metabolic substrates, and signalling modulators. We define the relationship between culture conditions and metabolic supplements in determining contractile maturation and sensitivity to IRI. Notably, we show that metabolic composition of the backbone medium establishes the baseline maturation state and determines responsiveness to additional maturation cues. These findings identify metabolic environment as a dominant regulator of injury susceptibility and provide a framework for improving the physiological fidelity of hiPSC-CM models of cardiac ischaemia.

cell biology↗

bioRxiv2025

Contractile function maintains cardiomyocyte differentiation and inhibits cell cycle activity

Numerous endotherm species lose cardiac regenerative capacity shortly after birth, which is in contrast to many ectotherm species who regenerate throughout life. Whether the enhanced contractile function required for endothermy contributes to the cell-cycle exit remains to be explored. Herein, we use human cardiac organoids with advanced maturation combined with direct targeting of contraction using mavacamten and aficamten to enable exquisite control of active contraction over brief time windows. We show that transient inhibition of contraction re-activates the cell cycle. Multi-omics analyses demonstrated the cell cycle response to be mediated through a dedifferentiation-like process, which was swiftly reversed upon removal of the myosin inhibitors. Together these findings reveal that active contraction maintains differentiation including cell cycle arrest in cardiomyocytes.

cell biology↗

bioRxiv2024

Epigenetic constraint of cellular genomes evolutionarily links genetic variation to function

Cellular diversity is a product of evolution acting to drive divergent regulatory programs from a common genome. Here, we use cross-cell-type epigenetic conservation to gain insight into the impact of selective constraints on genome function and phenotypic variation. By comparing chromatin accessibility across hundreds of diverse cell-types, we identify 1.4% of the human genome safeguarded by conserved domains of facultative heterochromatin, which we term regions under "cellular constraint". We calculate single-base resolution cellular constraint scores and demonstrate robust prediction of functionally important coding and non-coding loci in a cell-type-, trait-, and disease-agnostic manner. Cellular constraint annotation enhances causal variant identification, drug discovery, and clinical diagnostic predictions. Furthermore, cell-constrained sequences share paradoxical evolutionary signals of positive and negative selection, suggesting a dynamic role in driving human adaptation. Overall, this study demonstrates that evolutionary chromatin dynamics can be leveraged to inform the translation of genetic discoveries into effective biological, therapeutic, and clinical outcomes.

genetics↗

bioRxiv2024

A community-oriented, data-driven resource to improve protocol design for cardiac modelling from human pluripotent stem cells

Protocol design and benchmarking is central to optimising model development using human pluripotent stem cell derived cardiomyocytes (hPSC-CMs). By applying data mining to decades of research and hundreds of peer reviewed studies, we evaluate how protocol variables associate with common properties of cardiac functional and physiological maturation. This resource is publicly accessible through CMPortal, a community-oriented website that provides data-driven tools for researchers to navigate leverage decades of knowledge for benchmarking protocol designs and outcomes for their dedicated applications in developmental biology, disease modelling, and drug screening.

developmental biology↗