A5042953301- Genomics and Chromatin Dynamics
- Cancer-related Molecular Pathways
- RNA Research and Splicing
- Epigenetics and DNA Methylation
- Single-cell and spatial transcriptomics
- Genomic variations and chromosomal abnormalities
- Chromosomal and Genetic Variations
- Chromatin Remodeling and Cancer
- RNA and protein synthesis mechanisms
- CRISPR and Genetic Engineering
- Molecular Biology Techniques and Applications
- RNA modifications and cancer
- Gene Regulatory Network Analysis
- Genetics and Neurodevelopmental Disorders
- Bioinformatics and Genomic Networks
- Chronic Lymphocytic Leukemia Research
- Cancer Genomics and Diagnostics
- Plant Molecular Biology Research
- Advanced Fluorescence Microscopy Techniques
- Cell Image Analysis Techniques
Stanford University
2017-2024
Center for Systems Biology
2017-2020
Harvard University
2017-2020
SIB Swiss Institute of Bioinformatics
2019
École Polytechnique Fédérale de Lausanne
2019
Harvard University Press
2019
Animal genomes are organized into topologically associated domains (TADs). TADs thought to contribute gene regulation by facilitating enhancer-promoter (E-P) contacts within a TAD and preventing these across borders. However, the absolute difference in contact frequency boundaries is usually less than 2-fold, even though disruptions of borders can change expression 10-fold. Existing models fail explain this hypersensitive response. Here, we propose futile cycle model enhancer-mediated that...
Combinatorial interactions among transcription factors (TFs) play essential roles in generating gene expression specificity and diversity metazoans. Using yeast 2-hybrid (Y2H) assays on nearly all sequence-specific Drosophila TFs, we identified 1,983 protein-protein (PPIs), more than doubling the number of currently known PPIs TFs. For quality assessment, validated a subset our using MITOMI bimolecular fluorescence complementation assays. We combined interactome with prior PPI data to...
Summary Regulation of gene expression hinges on the interplay between enhancers and promoters, traditionally explored through pairwise analyses. Recent advancements in mapping genome folding, like GAM, SPRITE, multi-contact Hi-C, have uncovered multi-way interactions among super-enhancers (SEs), spanning megabases, yet not measured their frequency single cells or relationship clustering transcription. To close this gap, here we used multiplexed imaging to map 3D positions 376 SEs across...
Abstract Background The tumor suppressor p53 is a major regulator of the DNA damage response and has been suggested to selectively bind activate cell-type specific gene expression programs. However recent studies meta-analyses genomic data propose largely uniform, condition independent binding thus question selective dependent function p53. Results To systematically assess specificity p53, we measured its association with in 12 wild-type cancer cell lines, from range epithelial linages,...
Multiplexed DNA fluorescence in situ hybridization (FISH) imaging technologies have been developed to map the folding of chromatin fibers at tens nanometers and up several kilobases resolution single cells. However, computational methods reliably identify loops from such datasets are still lacking. Here we present a Single-Nucleus Analysis Pipeline for multiplexed FISH (SnapFISH), process data loops. SnapFISH can known mouse embryonic stem cells with high sensitivity accuracy. In addition,...
Abstract While population level analyses reveal significant roles for CTCF and cohesin in mammalian genome organization, their contribution to chromatin structure gene regulation at the single-cell remain incompletely understood 1–4 . Here, we use a super-resolution microscopy approach, Optical Reconstruction of Chromatin Architecture (ORCA) 5 measure effects removal or on folding across genomic scales. In untreated embryonic stem cells, observe intricate, frequently stacked loops which are...
Non-coding variants coordinate transcription factor (TF) binding and chromatin mark enrichment changes over regions spanning >100 kb. These molecularly coordinated are named "variable modules" (VCMs), providing a conceptual framework of how regulatory variation might shape complex traits. To better understand the molecular mechanisms underlying VCM formation, here, we mechanistically dissect VCM-modulating noncoding variant that is associated with reduced chronic lymphocytic leukemia (CLL)...
Abstract Repressive chromatin modifications are thought to compact silence transcription. However, it is unclear how structure changes during silencing and epigenetic memory formation. We measured gene expression in single cells after recruitment release of repressors at a reporter gene. Chromatin heterogeneous, with open conformations present both active silent states. Recruitment associated produces compaction across 10-20 kilobases, while reversible does not cause this scale. inherited,...
Abstract Transcription factors (TFs) and transcriptional coregulators represent an emerging class of therapeutic targets in oncology. Gene regulatory networks (GRNs) can be used to evaluate pharmacological agents targeting these identify drivers disease drug resistance. However, GRN methods that rely solely on gene expression often fail account for post-transcriptional modulation TF function. We present Epiregulon, a method constructs GRNs from single-cell ATAC-seq RNA-seq data accurate...
Abstract Animal genomes are organized into topologically associated domains (TADs), which exhibit more intra-domain than inter-domain contact. However, the absolute difference in contact is usually no twofold, even though disruptions to TAD boundaries can change gene expression by 8-10 fold. Existing models fail explain this superlinear transcriptional response changes genomic Here, we propose a futile cycle model where an enzyme stimulated association with its products bistability and...
Abstract The mammalian SWI/SNF, or BAF complex, has a conserved and direct role in antagonizing polycomb-mediated repression. Yet, appears to also promote repression by polycomb stem cells cancer. How both antagonizes promotes remains unknown. Here, we utilize targeted protein degradation dissect the BAF-polycomb axis embryonic on timescale of hours. We report that rapid depletion redistributes PRC1 PRC2 complexes from highly occupied domains, like Hox clusters, weakly sites are normally...
Abstract The tumor suppressor p53 is a major regulator of the DNA damage response and has been suggested to selectively bind activate cell type specific gene expression programs, however recent studies meta-analyses genomic data propose largely uniform, condition independent, binding. To systematically assess specificity p53, we measured its association with in 12 wild-type lines, from range epithelial linages, ionizing radiation. We found that majority bound sites were occupied across all...
The tumor suppressor protein p53 is activated by a diverse repertoire of cellular stresses (e.g. oncogenic signalling, DNA damage) and as transcription factor induces the expression response pathways genes (including cell cycle arrest, senescence, apoptosis). While frequently lost during tumorigenesis, approximately 50% human tumors retain intact p53, potentially rendering them sensitive to p53-induced death radiotherapy. Recent single analysis from our lab has shown that irradiation cells...
Abstract The tumor suppressor protein p53 is activated by a diverse repertoire of cellular stresses (e.g. oncogenic signalling, DNA damage) and as transcription factor induces the expression response pathways genes (including cell cycle arrest, senescence, apoptosis). While frequently lost during tumorigenesis, approximately 50% human tumors retain intact p53, potentially rendering them sensitive to p53-induced death radiotherapy. Recent single analysis from our lab has shown that...