A5080546686- Pancreatic function and diabetes
- Epigenetics and DNA Methylation
- Diabetes and associated disorders
- Single-cell and spatial transcriptomics
- Histone Deacetylase Inhibitors Research
- Genomics and Chromatin Dynamics
- Neonatal Respiratory Health Research
- Immune Cell Function and Interaction
- Infant Nutrition and Health
- Adipose Tissue and Metabolism
- RNA Research and Splicing
- T-cell and B-cell Immunology
- Genetic Associations and Epidemiology
- Mitochondrial Function and Pathology
- Retinoids in leukemia and cellular processes
- Gene expression and cancer classification
- RNA modifications and cancer
- Electron Spin Resonance Studies
- Acute Myeloid Leukemia Research
- Machine Learning in Bioinformatics
- MicroRNA in disease regulation
- Pancreatic and Hepatic Oncology Research
- Genetic Syndromes and Imprinting
- Genetics and Neurodevelopmental Disorders
- Molecular Biology Techniques and Applications
Jackson Laboratory
2016-2025
UConn Health
2022-2025
Sema4 (United States)
2022
Farmington Community Library
2020
Boston College
2014-2016
University of Connecticut
2016
Blood glucose levels are tightly controlled by the coordinated action of at least four cell types constituting pancreatic islets. Changes in proportion and/or function these cells associated with genetic and molecular pathophysiology monogenic, type 1, 2 (T2D) diabetes. Cellular heterogeneity impedes precise understanding components each islet that govern (dys)function, particularly less abundant delta gamma/pancreatic polypeptide (PP) cells. Here, we report single-cell transcriptomes for...
<h3>Background</h3> A major cause of enteric infection, Gram-negative pathogenic bacteria activate mucosal inflammation through lipopolysaccharide (LPS) binding to intestinal toll-like receptor 4 (TLR4). Breast feeding lowers risk disease, and human milk modulates inflammation. <h3>Objective</h3> This study tested whether oligosaccharides (HMOSs) influence <i>Escherichia coli</i>-induced interleukin (IL)-8 release by epithelial cells (IECs), identified specific proinflammatory signalling...
EndoC-βH1 is emerging as a critical human β cell model to study the genetic and environmental etiologies of (dys)function diabetes. Comprehensive knowledge its molecular landscape lacking, yet required, for effective use this model. Here, we report chromosomal (spectral karyotyping), (genotyping), epigenomic (ChIP-seq ATAC-seq), chromatin interaction (Hi-C Pol2 ChIA-PET), transcriptomic (RNA-seq miRNA-seq) maps EndoC-βH1. Analyses these define known (e.g., PDX1 ISL1) putative PCSK1 mir-375)...
Abstract Detecting multiplets in single nucleus (sn)ATAC-seq data is challenging due to sparsity and limited dynamic range. AMULET (ATAC-seq MULtiplet Estimation Tool) enumerates regions with greater than two uniquely aligned reads across the genome effectively detect multiplets. We evaluate method by generating snATAC-seq human blood pancreatic islet samples. has high precision, estimated via donor-based multiplexing, recall, simulated multiplets, compared alternatives identifies most when...
Type 2 diabetes (T2D) is a complex disorder in which both genetic and environmental risk factors contribute to islet dysfunction failure. Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs), most of are noncoding, >200 loci T2D. Identification the putative causal variants their target genes whether they lead gain or loss function remains challenging. Here, we profiled chromatin accessibility pancreatic samples from 19 genotyped individuals identified...
Immune cell activation assays have been widely used for immune monitoring and understanding disease mechanisms. However, these are typically limited in scope. A holistic study of circulating responses to different activators is lacking. Here we developed a cost-effective high-throughput multiplexed single-cell RNA-seq combined with epitope tagging (CITE-seq) determine how classic T cells (anti-CD3 coupled anti-CD28) or monocytes (LPS) alter the composition transcriptional profiles peripheral...
Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences compromised mitochondria in tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages retrograde (mitonuclear) signaling program impairs cellular identity and maturity β-cells, hepatocytes, brown adipocytes. Targeted deficiency throughout pathway, genome integrity, dynamics, or turnover, impaired oxidative phosphorylation machinery, activating...
Alpha TC1 (αTC1) and Beta-TC-6 (βTC6) mouse islet cell lines are cellular models of (dys)function type 2 diabetes (T2D). However, genomic characteristics these cells, their similarities to primary alpha beta undefined. Here, we report the epigenomic (ATAC-seq) transcriptomic (RNA-seq) landscapes αTC1 βTC6 cells. Each exhibits hallmarks its counterpart including cell-specific expression (e.g., Pdx1) Arx) transcription factors (TFs), enrichment binding motifs for TFs in αTC1/βTC6...
Abstract β cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of expression Tet2 in regulating immune killing. is induced murine human with inflammation but its reduced surviving cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis not islet infiltrates do eliminate even though from the can transfer NOD/ scid recipients. recipients are protected disease by diabetogenic cells.Tet2-KO show IFNγ-induced...
Transcription factor (TF) footprinting uncovers putative protein–DNA binding via combined analyses of chromatin accessibility patterns and their underlying TF sequence motifs. footprints are frequently used to identify TFs that regulate activities cell/condition-specific genomic regions (target loci) in comparison control (background using standard enrichment tests. However, there is a strong association between the level GC content locus number types can be detected at this site....
Single cell RNA-sequencing (scRNA-seq) precisely characterizes gene expression levels and dissects variation in associated with the state (technical or biological) type of cell, which is averaged out bulk measurements. Multiple correlated sources contribute to single cells, makes their estimation difficult existing methods developed for batch correction (e.g., surrogate variable analysis (SVA)) that estimate orthogonal transformations these sources. We iteratively adjusted (IA-SVA) can...
Single-cell RNA-sequencing (scRNA-seq) technology enables studying gene expression programs from individual cells. However, these data are subject to diverse sources of variation, including 'unwanted' variation that needs be removed in downstream analyses (e.g. batch effects) and 'wanted' or biological associated with a cell type) precisely described. Surrogate variable analysis (SVA)-based algorithms, commonly used for correction more recently scRNA-seq data. interpreting whether variables...
Abstract Genetic and environmental factors both contribute to islet dysfunction failure, resulting in type 2 diabetes (T2D). The epigenome integrates these cues can be remodeled by genetic variation. However, our knowledge of how variants T2D disease state alter human chromatin landscape cis- regulatory element (RE) use is lacking. To fill this gap, we profiled analyzed accessibility maps from 19 genotyped individuals (5 with T2D) using ATAC-seq technology. Chromatin quantitative trait locus...
ABSTRACT Mitochondrial damage is a hallmark of metabolic diseases, including diabetes and dysfunction-associated steatotic liver disease, yet the consequences impaired mitochondria in tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages retrograde (mitonuclear) signaling program impairs cellular identity maturity across multiple tissues. Surprisingly, demonstrate defects machinery, which observe pancreatic β cells humans with type 2 diabetes,...
Abstract β cells may participate and contribute to their own demise during Type 1 diabetes (T1D). We identified a novel role of Tet2 in regulating immune killing cells. is induced murine human with inflammation but its expression reduced surviving Tet2-KO mice that receive WT bone marrow transplants develop insulitis not islet infiltrates do eliminate even though from the can transfer NOD/ scid recipients. show inflammatory genes, associated closed transcription factor binding sites....
Abstract Immune cell activation assays have been widely used for immune monitoring and understanding disease mechanisms. However, these are typically limited in scope. A holistic study of circulating responses to different activators is lacking. Here we developed a cost-effective high-throughput multiplexed single-cell RNA-seq combined with epitope tagging (CITE-seq) determine how classic T cells (anti-CD3 coupled anti-CD28) or monocytes (LPS) alter the composition transcriptional profiles...
ABSTRACT Transcription factor (TF) footprinting uncovers putative protein-DNA binding via combined analyses of chromatin accessibility patterns and their underlying TF sequence motifs. footprints are frequently used to identify TFs that regulate activities cell/condition-specific genomic regions (target loci) in comparison control (background using standard enrichment tests. However, there is a strong association between the level GC content locus number types can be detected at this site....
SUMMARY EndoC-βH1 is emerging as a critical human beta cell model to study the genetic and environmental etiologies of function, especially in context diabetes. Comprehensive knowledge its molecular landscape lacking yet required fully take advantage this model. Here, we report extensive chromosomal (spectral karyotyping), (genotyping), epigenetic (ChIP-seq, ATAC-seq), chromatin interaction (Hi-C, Pol2 ChIA-PET), transcriptomic (RNA-seq, miRNA-seq) maps Integrated analyses these define known...
ABSTRACT Similar to other droplet-based single cell assays, nucleus ATAC-seq (snATAC-seq) data harbor multiplets that confound downstream analyses. Detecting in snATAC-seq is particularly challenging due its sparsity and trinary nature (0 reads: closed chromatin, 1: open one allele, 2: both alleles), yet offers a unique opportunity infer when >2 uniquely aligned reads are observed at multiple loci. Here, we implemented the first read count-based multiplet detection method,...