A5018897294- Single-cell and spatial transcriptomics
- RNA Research and Splicing
- Acute Myeloid Leukemia Research
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- High Altitude and Hypoxia
- Immune cells in cancer
- Erythrocyte Function and Pathophysiology
- Neonatal Respiratory Health Research
- Immune Cell Function and Interaction
- Congenital Diaphragmatic Hernia Studies
- Glioma Diagnosis and Treatment
- Preterm Birth and Chorioamnionitis
- Cancer, Hypoxia, and Metabolism
- CRISPR and Genetic Engineering
- Cancer Genomics and Diagnostics
- Blood disorders and treatments
- Epigenetics and DNA Methylation
- Hippo pathway signaling and YAP/TAZ
- Extracellular vesicles in disease
- Cancer Cells and Metastasis
- Bacterial Genetics and Biotechnology
- Genomics and Phylogenetic Studies
- Cancer-related molecular mechanisms research
- Circadian rhythm and melatonin
Massachusetts General Hospital
2021-2025
Cincinnati Children's Hospital Medical Center
2017-2025
Harvard University
2021-2025
Children's Hospital & Medical Center
2022-2024
University of Cincinnati
2018-2023
University of Cincinnati Medical Center
2021-2022
Children's Medical Center
2017
Walker (United States)
2015
Indiana University – Purdue University Indianapolis
2015
Abstract While the majority of cells contain a single nucleus, cell types such as trophoblasts, osteoclasts, and skeletal myofibers require multinucleation. One advantage multinucleation can be assignment distinct functions to different nuclei, but comprehensive interrogation transcriptional heterogeneity within multinucleated tissues has been challenging due presence shared cytoplasm. Here, we utilized single-nucleus RNA-sequencing (snRNA-seq) determine extent diversity myofibers. Nuclei...
The Human Cell Atlas (HCA) is expected to facilitate the creation of reference cell profiles, marker genes, and gene regulatory networks that will provide a deeper understanding healthy disease types from clinical biospecimens. hematopoietic system includes dozens distinct, transcriptionally coherent types, including intermediate transitional populations have not been previously described at molecular level. Using first data release HCA bone marrow tissue project, we resolved common, rare,...
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a powerful tool for human disease modeling and therapeutic testing. However, their use remains limited by immaturity heterogeneity. To characterize the source of this heterogeneity, we applied complementary single-cell RNA-seq bulk technologies over time during hiPSC cardiac differentiation in adult heart. Using integrated transcriptomic splicing analysis, more than half dozen distinct populations were...
ABSTRACT Heart valve cells mediate extracellular matrix (ECM) remodeling during postnatal leaflet stratification, but phenotypic and transcriptional diversity of in development is largely unknown. Single cell analysis mouse heart was used to evaluate heterogeneity ECM morphogenesis. The transcriptomic single from day (P)7 P30 murine aortic (AoV) mitral (MV) valves uncovered distinct subsets melanocytes, immune endothelial present at P7 P30. By contrast, interstitial populations are different...
Megakaryocytic-erythroid progenitors (MEPs) give rise to the cells that produce red blood and platelets. Although mechanisms underlying megakaryocytic (MK) erythroid (E) maturation have been described, those controlling their specification from MEPs are unknown. Single-cell RNA sequencing of primary human MEPs, common myeloid (CMPs), megakaryocyte progenitors, E revealed a distinct transitional MEP signature. Inferred regulatory transcription factors (TFs) were associated with differential...
RNA interference (RNAi) mediates antiviral defense in many eukaryotes. Caenorhabditis elegans mutants that disable RNAi are more sensitive to viral infection. Many enhance have also been identified; these mutations may reveal genes normally down-regulated defense. About one-third of the score synMuv B genes, identified 30 years ago unrelated screens for increased growth factor signaling. encode dREAM complex chromatin-regulatory proteins found nearly all animals and plants. We show mRNAs...
Abstract To understand the molecular pathogenesis of human disease, precision analyses to define alterations within and between disease-associated cell populations are desperately needed. Single-cell genomics represents an ideal platform enable identification comparison normal diseased transcriptional populations. We created cellHarmony, integrated solution for unsupervised analysis, classification, types from diverse single-cell RNA-Seq datasets. cellHarmony efficiently accurately matches...
Highlights•TRAF6 is required for hematopoietic stem cell (HSC) homeostasis•TRAF6 regulates HSC quiescence, self-renewal, and differentiation•Deletion of TRAF6 results in loss fitness•TRAF6 maintains a minimal threshold level IKKβ/NF-κB signaling HSCSummaryBasal nuclear factor κB (NF-κB) activation homeostasis the absence inflammation; however, upstream mediators basal NF-κB are less well understood. Here, we describe as an essential regulator through NF-κB. Hematopoietic-specific deletion...
Abstract Despite growing awareness of the biologic features underlying MLL-rearranged leukemia, targeted therapies for this leukemia have remained elusive and clinical outcomes remain dismal. MBNL1, a protein involved in alternative splicing, is consistently overexpressed leukemias. We found that MBNL1 loss significantly impairs propagation murine human vitro vivo. Through transcriptomic profiling our experimental systems, we show leukemic cells, regulates splicing (predominantly intron...
The rapid proliferation of single-cell RNA-sequencing (scRNA-Seq) technologies has spurred the development diverse computational approaches to detect transcriptionally coherent populations. While complexity algorithms for detecting heterogeneity increased, most require significant user-tuning, are heavily reliant on dimension reduction techniques and not scalable ultra-large datasets. We previously described a multi-step algorithm, Iterative Clustering Guide-gene Selection (ICGS), which...
Abstract Mutations in the cardiac splicing factor RBM20 lead to malignant dilated cardiomyopathy (DCM). To understand mechanism of RBM20-associated DCM, we engineered isogenic iPSCs with DCM-associated missense mutations as well knockout (KO) iPSCs. iPSC-derived heart tissues made from these cell lines recapitulate contractile dysfunction DCM and reveal greater than KO. Analysis RNA binding by eCLIP reveals a gain-of-function preference mutant for 3′ UTR sequences that are shared amyotrophic...
Circadian rhythms regulate diverse aspects of gastrointestinal physiology ranging from the composition microbiota to motility. However, development intestinal circadian clock and detailed mechanisms regulating intestine remain largely unknown. In this report, we show that both pluripotent stem cell-derived human organoids engrafted into mice patient-derived enteroids possess demonstrate phase-dependent necrotic cell death responses Clostridium difficile toxin B (TcdB). Intriguingly, mouse...
Mouse kidney allografts are spontaneously accepted in select, fully mismatched donor-recipient strain combinations, like DBA/2J to C57BL/6 (B6), by natural tolerance. We previously showed renal grafts form aggregates containing various immune cells within 2 weeks posttransplant, referred as regulatory T cell–rich organized lymphoid structures, which a novel tertiary organ. To characterize the we performed single-cell RNA sequencing on CD45+ sorted from and rejected 1-week 6-months...
Emerging evidence suggests that peripheral immune cells contribute to Alzheimer's disease (AD) neuropathogenesis. Among these, mast are known for their functions in allergic reactions and neuroinflammation; however, little is about role AD. Here, we crossed 5XFAD mice with cell-deficient strains observed the effects on AD-related neuropathology cognitive impairment. We found cell depletion improved contextual fear conditioning without affecting cued conditioning, anxiety-like behavior, or...
Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that incurable with conventional therapy. Their incidence is increasing global population aging. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in patients MDS, their clinical features quite similar. Here, we show hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling both necessary sufficient to induce dysplastic cytopenic MDS phenotypes. The HIF1A...