A5019543573- Epigenetics and DNA Methylation
- Genetic Syndromes and Imprinting
- Genetic Associations and Epidemiology
- Identity, Memory, and Therapy
- Diet and metabolism studies
- MicroRNA in disease regulation
- RNA modifications and cancer
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Cancer-related molecular mechanisms research
- Renal and related cancers
- Molecular Biology Techniques and Applications
- Parathyroid Disorders and Treatments
- Birth, Development, and Health
- Receptor Mechanisms and Signaling
- Pancreatitis Pathology and Treatment
- Cardiomyopathy and Myosin Studies
- Pancreatic function and diabetes
- Cardiovascular Function and Risk Factors
- Protein Structure and Dynamics
- Genetics and Neurodevelopmental Disorders
- Nuclear Receptors and Signaling
- Bipolar Disorder and Treatment
- RNA Research and Splicing
- Phosphodiesterase function and regulation
- Pluripotent Stem Cells Research
Johns Hopkins University
2019-2024
Broad Institute
2024
Johns Hopkins Medicine
2019-2023
Lieber Institute for Brain Development
2019-2022
Abstract DNA methylation (DNAm) is an epigenetic regulator of gene expression and a hallmark gene-environment interaction. Using whole-genome bisulfite sequencing, we have surveyed DNAm in 344 samples human postmortem brain tissue from neurotypical subjects individuals with schizophrenia. We identify genetic influence on local levels throughout the genome, both at CpG sites CpH sites, 86% SNPs 55% CpGs being part quantitative trait loci (meQTLs). These associations can further be clustered...
Loss-of-function mutations in ZMYM2 are associated with an increased risk of schizophrenia (SCZ) and neurodevelopmental disorders (NDD). interacts proteins involved histone modification gene regulation, including LSD1 ADNP; however, its specific roles the brain remain poorly understood. In this multi-omics study, we demonstrate that heterozygous knockout Zmym2 mice results widespread disturbances expression affecting diverse molecular pathways, those related to modifications neuronal...
Schizophrenia is a severe mental illness with high heritability, but its underlying mechanisms are poorly understood. We meta-analyzed large-scale brain transcriptomic data from mice harboring individual loss-of-function mutations in seven schizophrenia risk genes (Akap11, Dagla, Gria3, Grin2a, Sp4, Srrm2, Zmym2). While all studied regions were affected, the striatum and thalamus emerged as key of convergence. Striatum showed downregulation synapse- oxidative phosphorylation-related gene...
There is growing evidence for the role of DNA methylation (DNAm) quantitative trait loci (mQTLs) in genetics complex traits, including psychiatric disorders. However, due to extensive linkage disequilibrium (LD) genome, it challenging identify causal genetic variations that drive DNAm levels by population-based association studies. This limits utility mQTLs fine-mapping risk underlying disorders identified genome-wide studies (GWAS). Here we present INTERACT, a deep learning model integrates...
DNA methylation (DNAm) is a key epigenetic regulator of gene expression across development. The developing prenatal brain highly dynamic tissue, but our understanding drivers variability development limited. We, therefore, assessed genomic at over 39 million sites in the cortex using whole-genome bisulfite sequencing and found loci regions which levels are We saw that DNAm these was associated with nearby enriched for enhancer chromatin states tissue. Additionally, were genes...
Loss-of-function mutations in AKAP11 (a protein kinase A (PKA)-binding protein) greatly increase the risk of bipolar disorder and schizophrenia. We conducted multi-omic analyses Akap11 mutant mouse brains report neurobiological functions consequences its absence. interacts with multiple proteins involved signaling proteostasis. In Akap11+/- Akap11-/- synapses, PKA levels were markedly elevated, many synaptic hyperphosphorylated at substrate sites. showed extensive transcriptomic changes,...
ABSTRACT Protein-truncating variants in GRIA3 (encoding the GluA3/GluR3 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors) are associated with substantially increased risk schizophrenia (SCZ). Here we characterized Gria3 mutant mice carrying a protein-truncating mutation that mimics SCZ-associated variant. Transcriptomic analysis revealed activity-regulated genes downregulated cortical regions, while immune and glia-related pathways exhibit...
Abstract Schizophrenia and bipolar disorder are highly heritable mental illnesses with unclear pathophysiology. Heterozygous loss-of-function mutations of Sp4 , a zinc-finger transcription factor, greatly increase risk schizophrenia disorder. To investigate the molecular functions in an unbiased manner vivo we performed multi-omics analyses mutant mice. Bulk single nucleus RNA-seq data showed prominent gene expression changes all brain regions most cell types, including neuronal non-neuronal...
IntroductionHeart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease no proven pharmacologic therapies. Cardiac amyloidosis shares common features of HFpEF, however endomyocardial biopsy data are only available on limited subsets HFpEF patients. To our knowledge, this the first study to comprehensively characterize for patients referred evaluation.MethodsWe included Johns Hopkins Clinic who underwent right heart catheterization and biopsy. diagnosis was based signs...
Abstract DNA methylation (DNAm) regulates gene expression and may represent gene-environment interactions. Using whole genome bisulfite sequencing, we surveyed DNAm in a large sample (n=344) of human brain tissues. We identify widespread genetic influence on local levels throughout the genome, with 76% SNPs 38% CpGs being part quantitative trait loci (meQTLs). These associations can further be clustered into regions that are differentially methylated by given SNP, highlighting putative...
Abstract Background: DNA methylation (DNAm) is a key epigenetic regulator of gene expression across development. The developing prenatal brain highly dynamic tissue, but our understanding drivers variability development limited. Results: We therefore assessed genomic at over 39 million sites in the cortex using whole genome bisulfite sequencing and found loci regions which levels are saw that DNAm these was associated with nearby enriched for enhancer chromatin states tissue. Additionally,...
Abstract DNA methylation (DNAm) is a key epigenetic regulator of gene expression across development. The developing prenatal brain highly dynamic tissue, but our understanding drivers variability development limited. We therefore assessed genomic at over 39 million sites in the cortex using whole genome bisulfite sequencing and found loci regions which levels are saw that DNAm these was associated with nearby enriched for enhancer chromatin states tissue. Additionally, were genes psychiatric...
Abstract Chronic kidney disease (CKD) progresses by replacement of functional tissue compartments with fibrosis, representing a maladaptive repair process. Shifting towards physiologically-intact architecture, rather than is key to blocking CKD progression. In this study, we developed fibrosis model that uses human induced pluripotent stem cell (iPSC)-based three-dimensional renal organoids, in which exogenous TGF-β1 induces production extracellular matrix. these TGF- β1 increased...
Abstract Antipsychotic drugs are the current first-line of treatment for schizophrenia and other psychotic conditions. However, their molecular effects on human brain poorly studied, due to difficulty tissue access confounders associated with disease status. Here we examine differences in gene expression DNA methylation positive antipsychotic drug toxicology status caudate nucleus. We find no genome-wide significant methylation, but abundant expression. These overall quite similar between...
ABSTRACT Cell-specific microRNA (miRNA) expression estimates are important in characterizing the localization of miRNA signaling within tissues. Much this data is obtained from cultured cells, a process known to significantly alter levels. Thus, our knowledge vivo cell poor. We previously demonstrated microdissection-miRNA-sequencing (xMD-miRNA-seq) as means acquire estimates, directly formalin fixed tissues, albeit with limited yield. Here we optimized each step xMD including tissue...