A5005710964- Congenital heart defects research
- Hippo pathway signaling and YAP/TAZ
- Congenital Heart Disease Studies
- Cardiac Fibrosis and Remodeling
- Genetics and Neurodevelopmental Disorders
- Hedgehog Signaling Pathway Studies
- RNA modifications and cancer
- Cancer-related gene regulation
- Tissue Engineering and Regenerative Medicine
- Neonatal Respiratory Health Research
- Cardiac electrophysiology and arrhythmias
- RNA Research and Splicing
- Chromosomal and Genetic Variations
- Epigenetics and DNA Methylation
- Signaling Pathways in Disease
- Zebrafish Biomedical Research Applications
- Cancer-related molecular mechanisms research
- Wnt/β-catenin signaling in development and cancer
- Pulmonary Hypertension Research and Treatments
- Fault Detection and Control Systems
- Genetic and Kidney Cyst Diseases
- Cardiomyopathy and Myosin Studies
- Atrial Fibrillation Management and Outcomes
- Cardiac Valve Diseases and Treatments
- Gene Regulatory Network Analysis
Baylor College of Medicine
2020-2024
University of Chicago
2014-2024
Baylor School
2023
Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only small fraction of disease. In multi-institutional cohort surveyed by exome sequencing, combining analysis 987 individuals (discovery 59 affected trios control trios, replication 100 singletons 533 unaffected singletons) we observe variation at novel known loci related to specific cardiac malformation the atrioventricular septal defect (AVSD)....
The Second Heart Field (SHF) has been implicated in several forms of congenital heart disease (CHD), including atrioventricular septal defects (AVSDs). Identifying the SHF gene regulatory networks required for septation is therefore an essential goal understanding molecular basis AVSDs. We defined a Hedgehog-dependent network using whole genome transcriptional profiling and GLI-chromatin interaction studies. Forkhead box transcription factors Foxf1a Foxf2 were identified as Hedgehog targets....
Codevelopment of the lungs and heart underlies key evolutionary innovations in transition to terrestrial life. Cardiac specializations that support pulmonary circulation, including atrial septum, are generated by second field (SHF) cardiopulmonary progenitors (CPPs). It has been presumed transcription factors required SHF for cardiac septation, e.g., Tbx5 , directly drive a morphogenesis gene-regulatory network. Here, we report instead TBX5 drives Wnt ligands initiate bidirectional signaling...
Atrioventricular septal defects (AVSDs) are a common severe form of congenital heart disease (CHD). In this study we identified deleterious non-synonymous mutations in two cilia genes, Dnah11 and Mks1, independent N-ethyl-N-nitrosourea-induced mouse mutant lines with heritable recessive AVSDs by whole-exome sequencing. Cilia required for left/right body axis determination second field (SHF) Hedgehog (Hh) signaling, find that affect these requirements differentially. Dnah11avc4 did not...
BACKGROUND: The Hippo pathway effector YAP (Yes-associated protein) plays an essential role in cardiomyocyte proliferation and heart regeneration. In response to physiological changes, moves out of the nucleus. pathophysiological mechanisms regulating subcellular localization after myocardial infarction remain poorly defined. METHODS: We identified acetylation at site K265 by vitro followed mass spectrometry analysis. used adeno-associated virus express YAP-containing mutations that either...
Rationale: The heartbeat is organized by the cardiac conduction system (CCS), a specialized network of cardiomyocytes. Patterning CCS into atrial node versus ventricular (VCS) components with distinct physiology essential for normal heartbeat. Distinct VCS has been recognized more than century, but molecular basis this regional patterning not well understood. Objective: To study genetic and genomic mechanisms underlying distinction investigate rhythm consequences failed patterning. Methods...
The gene regulatory networks that coordinate the development of cardiac and pulmonary systems are essential for terrestrial life but poorly understood. T-box transcription factor Tbx5 is critical both specification heart development, how these activities mechanistically integrated remains unclear. Here using Xenopus mouse embryos, we establish molecular links between retinoic acid (RA) signaling in mesoderm RA sonic hedgehog expression endoderm to unveil a conserved RA-Hedgehog-Wnt cascade...
The relationship between heart failure (HF) and atrial fibrillation (AF) is clear, with up to half of patients HF progressing AF. pathophysiological basis AF in the context presumed result from remodeling. Upregulation transcription factor FOG2 (friend GATA2; encoded by
Brugada syndrome (BrS) is an inherited arrhythmia caused by loss-of-function variants in the cardiac sodium channel gene
Abstract Cardiac fibrosis, a common pathophysiology associated with various heart diseases, occurs from the excess deposition of extracellular matrix (ECM) 1 . fibroblasts (CFs) are primary cells that produce, degrade, and remodel ECM during homeostasis tissue repair 2 Upon injury, CFs gain plasticity to differentiate into myofibroblasts 3 adipocyte-like 4,5 osteoblast-like 6 cells, promoting fibrosis impairing function 7 How maintain their cell state adapt upon injury not well defined....
Atrial fibrillation (AF), the most common sustained cardiac arrhythmia and a major risk factor for stroke, often arises through ectopic electrical impulses derived from pulmonary veins (PVs). Sequence variants in enhancers controlling expression of transcription PITX2, which is expressed cardiomyocytes (CMs) PV left atrium (LA), have been implicated AF predisposition. Single nuclei multiomic profiling RNA analysis chromatin accessibility combined with spectral clustering uncovered distinct...
Hippo signaling, an evolutionarily conserved kinase cascade involved in organ size control, plays key roles various tissue developmental processes, but its role craniofacial development remains poorly understood. Using the transgenic Wnt1-Cre2 driver, we inactivated signaling components Lats1 and Lats2 cranial neuroepithelium of mouse embryos found that double conditional knockout (DCKO) Lats1/2 resulted neural tube defects. DCKO mutant had microcephaly with delayed defective closure....
Nearly half of all individuals with Down Syndrome (DS) have some type congenital heart defect (CHD), suggesting that DS sensitizes to CHD but does not cause it. We used a common mouse model DS, the Ts65Dn mouse, study contribution Tbx5, known modifier CHD, defects on trisomic backgroun. Mice were heterozygous for Tbx5 null allele crossed mice. Thoraxes progeny fixed in 10% formalin, embedded paraffin, and sectioned analysis CHD. Gene expression embryonic hearts was examined by quantitative...
Mechanisms underlying distinct specification, commitment, and differentiation phases of cell fate determination remain undefined due to difficulties capturing these processes. Here, we interrogate the activity ETV2, a transcription factor necessary sufficient for hematoendothelial differentiation, within isolated intermediates. We observe transcriptional upregulation Etv2 opening ETV2-binding sites, indicating new ETV2 binding, in common cardiac-hematoendothelial progenitor population....
The Hippo pathway is critical to organ development, homeostasis, and regeneration, facilitated by YAP/TEAD-mediated gene expression. Although emerging studies report Hippo-YAP dysfunction after viral infection, it largely unknown in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we analyzed RNA sequencing data from SARS-CoV-2 infected human lung samples induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs), observed a decrease YAP target In...
Modulation of the heart’s immune microenvironment is crucial for recovery after ischemic events such as myocardial infarction (MI). Endothelial cells (ECs) can have regulatory functions; however, interactions between ECs and environment in heart MI remain poorly understood. We identified an EC-specific IFN responsive gene signature adult pediatric failure (HF) tissues. Single-cell transcriptomic analysis murine hearts subjected to uncovered EC population (IFN-ECs) with immunologic signatures...
SUMMARY Heterochrony, defined as differences in the timing of developmental processes, impacts organ development, homeostasis, and regeneration. The molecular basis heterochrony mammalian tissues is poorly understood. We report that Hedgehog signaling activates a heterochronic pathway controls differentiation multiple lineages. A trajectory from second heart field cardiac progenitors to first cardiomyocytes was identified by single-cell transcriptional profiling mouse embryos. survey...
The Hippo pathway is critical to organ development, homeostasis, and regeneration, facilitated by YAP/TEAD-mediated gene expression. Although emerging studies report Hippo-YAP dysfunction after viral infection, it largely unknown in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we analyzed RNA sequencing data from SARS-CoV-2 infected human lung samples induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs), observed a decrease YAP target In...
Abstract The Hippo pathway is critical to organ development, homeostasis, and regeneration, facilitated by YAP/TEAD-mediated gene expression. Although emerging studies report Hippo-YAP dysfunction after viral infection, it largely unknown in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we analyzed RNA sequencing data from SARS-CoV-2 infected human lung samples induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs), observed a decrease YAP target...