A5101854464- CRISPR and Genetic Engineering
- Pluripotent Stem Cells Research
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Epigenetics and DNA Methylation
- Gene Regulatory Network Analysis
- Pancreatic function and diabetes
- Single-cell and spatial transcriptomics
- Genetics and Neurodevelopmental Disorders
- Neurogenesis and neuroplasticity mechanisms
- Plant Molecular Biology Research
- FOXO transcription factor regulation
- Renal and related cancers
- Congenital heart defects research
- Virus-based gene therapy research
- Heat shock proteins research
- Immune Response and Inflammation
- Enzyme Structure and Function
- Acute Myeloid Leukemia Research
- Telomeres, Telomerase, and Senescence
- Endoplasmic Reticulum Stress and Disease
- Genetic Associations and Epidemiology
- Gene expression and cancer classification
- Genomics and Rare Diseases
- Glycosylation and Glycoproteins Research
Memorial Sloan Kettering Cancer Center
2016-2025
Kettering University
2022-2025
NYU Langone Health
2024
Precision for Medicine (United States)
2024
New York Proton Center
2022-2023
New York University
2020-2023
Sungkyunkwan University
2021
NYU Langone’s Laura and Isaac Perlmutter Cancer Center
2021
Cornell University
2019
Abstract The pace of human brain development is highly protracted compared with most other species 1–7 . maturation cortical neurons particularly slow, taking months to years develop adult functions 3–5 Remarkably, such timing retained in derived from pluripotent stem cells (hPSCs) during vitro differentiation or upon transplantation into the mouse 4,8,9 Those findings suggest presence a cell-intrinsic clock setting neuronal maturation, although molecular nature this remains unknown. Here we...
Transcriptional regulatory mechanisms of lineage priming in embryonic development are largely uncharacterized because the difficulty isolating transient progenitor populations. Directed differentiation human pluripotent stem cells (hPSCs) combined with gene editing provides a powerful system to define precise temporal requirements for progressive chromatin changes during cell fate transitions. Here, we map dynamic landscape associated sequential stages pancreatic from hPSCs. Our analysis...
Abstract CCCTC-binding factor (CTCF) is critical to three-dimensional genome organization. Upon differentiation, CTCF insulates active and repressed genes within Hox gene clusters. We conducted a genome-wide CRISPR knockout (KO) screen identify required for CTCF-boundary activity at the HoxA cluster, complemented by biochemical approaches. Among candidates, we identified Myc-associated zinc-finger protein (MAZ) as cofactor in insulation. MAZ colocalizes with chromatin borders and, similar...
Ongoing, early-stage clinical trials illustrate the translational potential of human pluripotent stem cell (hPSC)-based therapies in Parkinson's disease (PD). However, an unresolved challenge is extensive death following transplantation. Here, we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survival vivo. We identified p53-mediated apoptotic as major contributor loss and uncovered causal link tumor necrosis factor alpha (TNF-α)-nuclear κB (NF-κB) signaling...
Partitioning of repressive from actively transcribed chromatin in mammalian cells fosters cell-type-specific gene expression patterns. While this partitioning is reconstructed during differentiation, the occupancy key insulator, CCCTC-binding factor (CTCF), unchanged at developmentally important Hox clusters. Thus, dynamic changes boundaries must entail other activities. Given its requirement for loop formation, we examined cohesin-based without known insulators, CTCF and Myc-associated...
Abstract The pace of human brain development is highly protracted compared to most other species. maturation cortical neurons particularly slow, extending over months years reach adult-like functions. Remarkably, such timing retained in derived from pluripotent stem cell (hPSC) during vitro differentiation or upon transplantation into the murine vivo . Those findings suggest presence a intrinsic clock that sets neuronal maturation, though molecular nature has remained elusive. Here, we...
Functional enhancer annotation is critical for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants. However, unbiased discovery in disease-relevant contexts remains challenging. To identify enhancers pertinent to diabetes, we conducted a CRISPR interference (CRISPRi) screen the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among identified, focused on an named ONECUT1e-664kb, ∼664 kb from ONECUT1 promoter....
While clinical trials are ongoing using human pluripotent stem cell-derived midbrain dopamine (mDA) neuron precursor grafts in Parkinson's disease (PD), current protocols to derive mDA neurons remain suboptimal. In particular, the yield of TH+ after vivo grafting and expression some subtype-specific markers can be further improved. For example, characterization by single cell transcriptomics has yielded only a small proportion considerable fraction contaminating populations. Here we present...
Abstract Substantial progress has been made in understanding how tumors escape immune surveillance. However, few measures to counteract tumor evasion have developed. Suppression of antigen expression is a common adaptive mechanism that cancers use evade detection and destruction by the system. Epigenetic modifications play critical role various aspects invasion, including regulation expression. To identify epigenetic regulators expression, we established transplantable syngeneic model with...
FBXO31 is the substrate receptor of one many CUL1-RING ubiquitin ligase (CRL1) complexes. Here, we show that low mRNA levels are associated with high pre-operative prostate-specific antigen (PSA) and Gleason grade in human prostate cancer. Mechanistically, CRL1
Directed differentiation of pluripotent stem cells (PSCs) is a powerful model system for deconstructing embryonic development. Although mice are the most advanced mammalian genetic studies development, state-of-the-art protocols directed mouse PSCs into defined lineages require additional steps and generates target cell types with lower purity than analogous human PSCs, limiting their application as models mechanistic Here, we examine potential epiblast cultured in media containing Wnt...
The directed differentiation of pluripotent stem cells (PSCs) from panels genetically diverse individuals is emerging as a powerful experimental system for characterizing the impact natural genetic variation on developing cell types and tissues. Here, we establish new PSC lines approaches modeling embryonic development in diverse, outbred mouse stock (Diversity Outbred mice). We show that range inbred can be stably maintained primed state (epiblast -- EpiSCs) contribution to phenotypic...
Pluripotent stem cells have remarkable self-renewal capacity: the ability to proliferate indefinitely while maintaining pluripotent identity essential for their differentiate into almost any cell type in body. To investigate interplay between these two aspects of self-renewal, we perform four parallel genome-scale CRISPR-Cas9 loss-of-function screens interrogating fitness hPSCs and dissolution primed during early differentiation. These distinguish genes with distinct roles pluripotency...
Abstract Ongoing, first-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based therapies in Parkinson’s disease (PD). However, a major unresolved challenge field is extensive death following transplantation with <10% grafted dopamine neurons surviving. Here, we performed pooled CRISPR/Cas9 screen to enhance survival postmitotic vivo . We identified p53-mediated apoptotic as contributor neuron loss uncovered causal link...
Comprehensive enhancer discovery is challenging because most enhancers, especially those affected in complex diseases, have weak effects on gene expression. Our network modeling revealed that nonlinear enhancer-gene regulation during cell state transitions can be leveraged to improve the sensitivity of discovery. Utilizing hESC definitive endoderm differentiation as a dynamic transition system, we conducted mid-transition CRISPRi-based screen. The screen discovered comprehensive set...
SUMMARY Partitioning of repressive from actively transcribed chromatin in mammalian cells fosters cell-type specific gene expression patterns. While this partitioning is reconstructed during differentiation, the occupancy key insulator, CTCF, unchanged at developmentally important Hox clusters. Thus, dynamic changes boundaries must entail other activities. Given its requirement for loop formation, we examined cohesin-based without known insulators, CTCF and MAZ, identified a family zinc...
ABSTRACT The mechanisms underlying the ability of embryonic stem cells (ESCs) to rapidly activate lineage-specific genes during differentiation remain largely unknown. Through multiple CRISPR-activation screens, we discovered human ESCs have pre-established transcriptionally competent chromatin regions (CCRs) that support gene expression at levels comparable differentiated cells. CCRs reside in same topological domains as their target genes. They lack typical enhancer-associated histone...