Biology subjects

Kathiriya, I. S.

Publications and source records attributed to Kathiriya, I. S..

8 recordsLinked to original sources

bioRxiv2026

Neural Crest-Derived Endocardial Cells Required for Heart Valve Development

Abnormalities in cardiac valves, which maintain unidirectional blood flow through the heart, affect 2-3% of people worldwide and are the most common form of structural heart disease (1).Yet the cell types that make up the valve, and how they communicate to direct development and homeostasis, remain poorly understood. Here, we identify a rare, essential population of highly secretory valve endocardial cells in mouse and human that derive from migrating neural crest cells. Ablation of these cells in mice caused perinatal lethality with thickened leaflets, stenosis, and regurgitation, mirroring human valve disease. This subset of endocardial cells uniquely expresses the secreted signaling protein parathyroid hormone-like hormone (Pthlh). Global disruption of Pthlh caused valve stenosis and lethality and neural crest-specific deletion produced similar valve disease, with impaired maturation of valvular interstitial cells and disrupted bone morphogenetic protein signaling. These findings identify a previously unrecognized cell type and signaling pathway essential for valve morphogenesis, with implications for the pathogenesis and treatment of human valve defects.

developmental biology↗

bioRxiv2026

Network-enabled drug repurposing identifies lithium to promote cardiomyocyte proliferation

The adult mammalian heart has minimal regenerative capacity, limited in part by endogenous cardiomyocyte (CM) renewal. Although CM proliferation is a promising target in both congenital and adult heart disease, no current therapies specifically target this process. Progress has been hindered by the complexity of CM proliferation signaling networks, which may require systems-level approaches. The overall goal of this study was to leverage systems modeling to identify FDA approved drugs that have the potential to be repurposed towards CM proliferation. To achieve this goal, we developed a computational drug repurposing framework that integrates drug-target interaction data with a previously developed logic-based network model of CM proliferation signaling. Using this framework, we identified 81 drugs that directly target nodes within the CM proliferation network, corresponding to 32 unique drug-target interactions. Virtual screening predicted 5 unique drug-target interactions that increase CM proliferation and 14 that decrease CM proliferation outputs. Lithium, a GSK3{beta} inhibitor widely prescribed for bipolar disorder, was predicted and experimentally validated to promote CM proliferation through a Cyclin D/CDK4 pathway. In vivo, treatment of pregnant mice with lithium increased DNA synthesis in the CMs of their embryos. A retrospective analysis of the FDA Adverse Events Reporting System confirmed that relative to other mood stabilizers, in utero exposure to lithium was associated with an increased incidence of congenital heart defects, in males but not females. Together, this work provides a computational-experimental framework for repurposing FDA-approved drugs to modulate CM proliferation, which highlights therapeutic potential of lithium for adult CM regeneration but congenital risks to developing embryos.

systems biology↗

bioRxiv2025

Reduced TBX5 dosage undermines developmental control of atrial cardiomyocyte identity in a model of human atrial disease

While atrial septal defects (ASDs) and atrial fibrillation (AF) present differently, there is evidence that they share some genetic basis. Here, we used directed differentiation of human induced pluripotent stem cells into atrial or ventricular cardiomyocytes (CMs) to delineate gene regulatory networks (GRNs) that define each identity. We uncovered accessible chromatin regions, transcription factor motifs and key regulatory nodes specific to, or shared by, both CM types, including the transcription factor TBX5, which is linked to genetic susceptibility of ASDs and AF in humans. Complete TBX5 loss resulted in a near absence of atrial CMs with a concomitant increase in the abundance of other cell types. Reduced dosage of TBX5 in human atrial CMs caused cellular, electrophysiologic and molecular phenotypes consistent with features of atrial CM dysfunction. This included dose-dependent aberrant accessibility of many chromatin regions and perturbation of gene regulatory networks of atrial CM identity. These results suggest that, in addition to stemming from ion channel or extracellular matrix dysfunction, atrial diseases such as ASDs or AF may result from disruptions of atrial CM identity.

developmental biology↗

bioRxiv2025

Dose-dependent sensitivity of human 3D chromatin to a heart disease-linked transcription factor

Dosage-sensitive transcription factors (TFs) underlie altered gene regulation in human developmental disorders, and cell-type specific gene regulation is linked to the reorganization of 3D chromatin during cellular differentiation. Here, we show dose-dependent regulation of chromatin organization by the congenital heart disease (CHD)- linked, lineage-restricted TF TBX5 in human cardiomyocyte differentiation. Genome organization, including compartments, topologically associated domains, and chromatin loops, are sensitive to reduced TBX5 dosage in a human model of CHD, with variations in response across individual cells. Regions normally bound by TBX5 are especially sensitive, while co-occupancy with CTCF partially protects TBX5-bound TAD boundaries and loop anchors. These results highlight the importance of lineage-restricted TF dosage in cell-type specific 3D chromatin dynamics, suggesting a new mechanism for TF-dependent disease.

genomics↗

bioRxiv2024

A TBX5-dependent compartment boundary patterns the cardiac interventricular septum

Failure of septation of the interventricular septum (IVS) is the most common congenital heart defect (CHD), but mechanisms for patterning the IVS are largely unknown. Here, we show that a Tbx5+/Mef2cAHF+ progenitor lineage forms a compartment boundary bisecting the IVS. This coordinated population originates at a first- and second heart field interface. Ablation of Tbx5+/Mef2cAHF+ progenitors cause IVS disorganization, right ventricular hypoplasia and mixing of IVS lineages. Reduced dosage of the CHD transcription factor TBX5 disrupts boundary position and integrity, resulting in ventricular septation defects (VSDs) and patterning defects, including misexpression of Slit2 and Ntn1, which encode guidance cues. Reducing NTN1 dosage partly rescues cardiac defects in Tbx5 mutant embryos. Loss of Slit2 or Ntn1 causes VSDs and perturbed septal lineage distributions. Thus, we identify Tbx5 as a candidate selector gene, directing progenitors and regulating essential cues, to pattern a compartment boundary for proper cardiac septation, revealing mechanisms for cardiac birth defects.

developmental biology↗

bioRxiv2020

Cell Layers: Uncovering clustering structure and knowledge in unsupervised single-cell transcriptomic analysis

MotivationUnsupervised clustering of single-cell transcriptomics is a powerful method for identifying cell populations. Static visualization techniques for single-cell clustering only display results for a single resolution parameter. Analysts will often evaluate more than one resolution parameter, but then only report one. ResultsWe developed Cell Layers, an interactive Sankey tool for the quantitative investigation of gene expression, coexpression, biological processes, and cluster integrity across clustering resolutions. Cell Layers enhances the interpretability of single-cell clustering by linking molecular data and cluster evaluation metrics, to provide novel insight into cell populations. Availability and implementationUpon request

bioinformatics↗

bioRxiv2020

Chromatin remodeler Brahma safeguards canalization in cardiac mesoderm differentiation

Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1-4. Canalization is essential for stabilizing cell fate, but the mechanisms underlying robust canalization are unclear. Here we show that deletion of the BRG1/BRM-associated factor (BAF) chromatin remodeling complex ATPase gene Brm (encoding Brahma) results in a radical identity switch during directed cardiogenesis of mouse embryonic stem cells (ESCs). Despite establishment of well-differentiated precardiac mesoderm, Brm-null cells subsequently shifted identities, predominantly becoming neural precursors, violating germ layer assignment. Trajectory inference showed sudden acquisition of non-mesodermal identity in Brm-null cells, consistent with a new transition state inducing a fate switch referred to as a saddle-node bifurcation3,4. Mechanistically, loss of Brm prevented de novo accessibility of cardiac enhancers while increasing expression of the neurogenic factor POU3F1 and preventing expression of the neural suppressor REST. Brm mutant identity switch was overcome by increasing BMP4 levels during mesoderm induction, repressing Pou3f1 and re-establishing a cardiogenic chromatin landscape. Our results reveal BRM as a compensable safeguard for fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory that must be safeguarded, with implications in development and disease.

developmental biology↗

bioRxiv2019

A TBX5 dosage-sensitive gene regulatory network for human congenital heart disease

Haploinsufficiency of transcriptional regulators causes human congenital heart disease (CHD). However, underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define transcriptional consequences of reduced dosage of the CHD-linked transcription factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways-- including lineage decisions and genes associated with cardiomyocyte function and CHD genetics--in discrete subpopulations of cardiomyocytes. GRN analysis identified vulnerable nodes enriched for CHD genes, indicating that cardiac network stability is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between Tbx5 and Mef2c was validated in mouse, manifesting as ventricular septation defects. These results demonstrate exquisite sensitivity to TBX5 dosage by diverse transcriptional responses in heterogeneous subsets of iPSC-derived cardiomyocytes. This predicts candidate GRNs for human CHDs, with implications for quantitative transcriptional regulation in disease.

developmental biology↗