A5062993477- Genomics and Chromatin Dynamics
- DNA Repair Mechanisms
- Epigenetics and DNA Methylation
- CRISPR and Genetic Engineering
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA modifications and cancer
- Single-cell and spatial transcriptomics
- RNA Research and Splicing
- Cancer Genomics and Diagnostics
- Genetics and Neurodevelopmental Disorders
- RNA and protein synthesis mechanisms
- Genomics and Phylogenetic Studies
- Chromosomal and Genetic Variations
- Immune Response and Inflammation
- Neurological Disease Mechanisms and Treatments
- Inflammation biomarkers and pathways
- Genomic variations and chromosomal abnormalities
- Telomeres, Telomerase, and Senescence
- DNA and Biological Computing
- Tryptophan and brain disorders
- Pluripotent Stem Cells Research
- Genetics, Bioinformatics, and Biomedical Research
- Molecular Biology Techniques and Applications
- NF-κB Signaling Pathways
- Mitochondrial Function and Pathology
Massachusetts Institute of Technology
2020-2023
Institute of Cognitive and Brain Sciences
2023
Florida State University
2012-2022
Fred Hutch Cancer Center
2012
Vellore Institute of Technology University
2009
Abstract The human and mouse genomes contain instructions that specify RNAs proteins govern the timing, magnitude, cellular context of their production. To better delineate these elements, phase III Encyclopedia DNA Elements (ENCODE) Project has expanded analysis cell tissue repertoires RNA transcription, chromatin structure modification, methylation, looping, occupancy by transcription factors RNA-binding proteins. Here we summarize efforts, which have produced 5,992 new experimental...
Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half genome switching during development, primarily units of 400-800 kilobases ('replication domains'), whose positions are preserved different cell types, conserved between species, and appear to confine long-range effects chromosome rearrangements. Early late correlate, respectively, open closed three-dimensional chromatin...
DNA replication is temporally and spatially organized in all eukaryotes, yet the molecular control biological function of replication-timing program are unclear. Rif1 required for normal genome-wide regulation timing, but its poorly understood. Here we show that mouse embryonic stem cells, coats late-replicating domains and, with Lamin B1, identifies most genome. an essential determinant timing non-Lamin B1-bound late domains. We further demonstrate defines restricts interactions between...
The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal developing a comprehensive map functional elements human genome. These included genes, biochemical regions associated gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) transcript isoforms. marks serve as sites for candidate cis-regulatory (cCREs) that may roles regulating expression1. project has been extended to model organisms, particularly mouse. In...
Abstract ENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds cell types, providing a universal annotation for genome interpretation. However, particular applications, it may be advantageous to use customized annotation. Here, we develop such custom by leveraging advanced assays, as eCLIP, Hi-C, whole-genome STARR-seq on number data-rich types. A key aspect this is comprehensive experimentally derived networks both transcription factors RNA-binding...
Recent work has identified dozens of non-coding loci for Alzheimer's disease (AD) risk, but their mechanisms and AD transcriptional regulatory circuitry are poorly understood. Here, we profile epigenomic transcriptomic landscapes 850,000 nuclei from prefrontal cortexes 92 individuals with without to build a map the brain regulome, including profiles, regulators, co-accessibility modules, peak-to-gene links in cell-type-specific manner. We develop methods multimodal integration detecting...
Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer's disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq human postmortem prefrontal cortex samples and found that excitatory AD were enriched for somatic mosaic gene fusions. Gene fusions particularly damage repair senescence signatures. In addition, structural variations burdened DSBs CK-p25 mouse model...
Mammalian genomes are partitioned into domains that replicate in a defined temporal order. These can at similar times all cell types (constitutive) or type-specific (developmental). Genome-wide chromatin conformation capture (Hi-C) has revealed sub-megabase topologically associating (TADs), which the structural counterparts of replication domains. Hi-C also segregates inter-TAD contacts 3D spatial compartments align precisely to genome-wide timing profiles. Determinants replication-timing...
Mammalian DNA replication is regulated via multi-replicon segments that replicate in a defined temporal order during S-phase. Further, early/late of RDs corresponds to active/inactive chromatin interaction compartments. Although origins are selected stochastically, variation timing poorly understood. Here we devise strategy measure using copy number single mouse embryonic stem cells. We find borders between replicated and unreplicated highly conserved cells, demarcating active inactive...
Down syndrome (DS) is a genetic disorder driven by the triplication of chromosome 21 (T21) and characterized wide range neurodevelopmental physical disabilities. Transcriptomic analysis tissue samples from individuals with DS has revealed that T21 induces genome-wide transcriptional disruption. However, consequences on nuclear architecture its interplay transcriptome remain unknown. In this study, we find unlike human induced pluripotent stem cells (iPSCs), iPSC-derived neural progenitor...
DNA double-strand breaks (DSBs) are linked to neurodegeneration and senescence. However, it is not clear how DSB-bearing neurons influence neuroinflammation associated with neurodegeneration. Here, we characterize from the CK-p25 mouse model of using single-nucleus, bulk, spatial transcriptomic techniques. enter a late-stage damage response marked by nuclear factor κB (NFκB)-activated senescent antiviral immune pathways. In humans, Alzheimer's disease pathology closely activation in...
Abstract Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer's disease (AD). A number mutations microglial protein triggering receptor expressed on myeloid cells 2 (TREM2) been associated with increased risk developing AD, most notably R47H/+ substitution. We employed gene editing and stem cell models to gain insight into effects TREM2 mutation human‐induced pluripotent cell‐derived microglia. found transcriptional...
Several 400- to 800-kb murine chromosome domains switch from early late replication during loss of pluripotency, accompanied by a stable form gene silencing that is resistant reprogramming. We found that, whereas enhanced nuclease accessibility correlated with genome-wide, timing differentiation were exceptionally inaccessible even when early-replicating. Nonetheless, two studied in detail exhibited substantial changes transcriptional activity and higher-order chromatin unfolding confined...
Chromatin profiling in single cells has been extremely challenging and almost exclusively limited to histone proteins. In cases where single-cell methods have shown promise, many require highly specialized equipment or cell type-specific protocols are relatively low throughput. Here, we combine the advantages of tagmentation, linear amplification, combinatorial indexing produce a high-throughput DNA binding site mapping method that is simple, inexpensive, capable multiplexing several...
The temporal order of DNA replication is regulated during development and highly correlated with gene expression, histone modifications 3D genome architecture. We tracked changes in timing, chromatin conformation capture (Hi-C) A/B compartments over the first two cell cycles differentiation human embryonic stem cells to definitive endoderm. Remarkably, transcriptional programs were irreversibly reprogrammed within cycle largely but not universally coordinated timing changes. Moreover,...
Cellular differentiation and reprogramming are accompanied by changes in replication timing 3D organization of large-scale (400 to 800 Kb) chromosomal domains ('replication domains'), but few gene products have been identified whose disruption affects these properties.Here we show that deletion esBAF chromatin-remodeling complex components BAF250a Brg1, not BAF53a, disrupts at specific domains. Also, BAF250a-deficient fibroblasts reprogrammed a pluripotency-like state failed reprogram many...
Abstract Structural variants can contribute to oncogenesis through a variety of mechanisms, yet, despite their importance, the identification structural in cancer genomes remains challenging. Here, we present an integrative framework for comprehensively identifying variation genomes. For first time, apply next-generation optical mapping, high-throughput chromosome conformation capture (Hi-C), and whole genome sequencing systematically detect SVs cells. Using this approach, identify...
Replication timing (RT) is the temporal order in which genomic DNA replicated during S phase. Early and late replication correlate with transcriptionally active inactive chromatin compartments, but mechanistic links between large-scale chromosome structure, transcription, are still enigmatic. A proper RT program necessary to maintain global epigenome that defines cell identity, suggesting critical for integrity by facilitating assembly of different types at times regulated development has...