A5021926957- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Histone Deacetylase Inhibitors Research
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- CRISPR and Genetic Engineering
- Protein Degradation and Inhibitors
- Acute Myeloid Leukemia Research
- Chemical Synthesis and Analysis
- Biochemical and Molecular Research
- Genetics and Neurodevelopmental Disorders
- Virus-based gene therapy research
- RNA Research and Splicing
- Viral Infectious Diseases and Gene Expression in Insects
- Cancer-related gene regulation
- Genetic Syndromes and Imprinting
- Ubiquitin and proteasome pathways
Harvard University
2017-2025
Broad Institute
2022-2025
Brigham and Women's Hospital
2025
Probing base editing outcomes leads to new C:G T:A editors with greater efficiency and product purity, fewer indels.
Abstract UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal 1 . By co-opting KBTBD4, substrate receptor the CUL3–RING E3 ubiquitin ligase (CRL3) complex, promotes degradation LSD1–CoREST corepressor thereby limiting attrition 2,3 However, direct target and mechanism action remain unclear. Here we show that acts as molecular glue to induce high-affinity interactions between KBTBD4 HDAC1/2 promote degradation. Through proteomics chemical inhibitor studies,...
Chromatin modifiers often work in concert with transcription factors (TFs) and other complex members, where they can serve both enzymatic scaffolding functions. Due to this, active site inhibitors targeting chromatin may perturb nonenzymatic For instance, the antiproliferative effects of active-site lysine-specific histone demethylase 1A (LSD1) are driven by disruption a protein-protein interaction growth factor independence 1B (GFI1B) rather than inhibition activity. Recently,...
Abstract Chromatin regulators are frequently mutated in human cancer and attractive drug targets. They include diverse proteins that share functional domains assemble into related multi-subunit complexes. To investigate relationships among these regulators, here we apply combinatorial CRISPR knockouts (KOs) to test over 35,000 gene-gene pairings leukemia cells, using a library of 300,000 constructs. Top pairs demonstrate either compensatory non-lethal interactions or synergistic lethality...
Cycloheximide (CHX) is an inhibitor of eukaryotic translation elongation that has played essential role in the study protein synthesis. Despite its ubiquity, few studies have been directed towards accessing synthetic CHX derivatives, even though such efforts may lead to synthesis inhibitors with improved or alternate properties. Described here total and analogues, establishment structure-activity relationships (SAR) responsible for inhibition. The SAR aided design more potent compounds, one...
Abstract The insulator protein CTCF is essential for mediating chromatin loops and regulating gene expression. While it established that DNA methylation hinders binding, the impacts of this methylation-sensitive binding on architecture transcription are poorly defined. Here, we used a selective DNMT1 inhibitor to investigate characteristics functions ‘reactivated’ peaks resulting from global demethylation. We found reactivated preferentially form bodies interact with highly-looping partner...
Abstract Cycloheximide (CHX) is an inhibitor of eukaryotic translation elongation that has played essential role in the study protein synthesis. Despite its ubiquity, few studies have been directed towards accessing synthetic CHX derivatives, even though such efforts may lead to synthesis inhibitors with improved or alternate properties. Described here total and analogues, establishment structure–activity relationships (SAR) responsible for inhibition. The SAR aided design more potent...
UM171 is a potent small molecule agonist of ex vivo human hematopoietic stem cell (HSC) self-renewal, process that tightly controlled by epigenetic regulation. By co-opting KBTBD4, substrate receptor the CULLIN3-RING E3 ubiquitin ligase complex, promotes degradation members CoREST transcriptional corepressor thereby limiting HSC attrition. However, direct target and mechanism action remain unclear. Here, we reveal acts as molecular glue to induce high-affinity interactions between KBTBD4...
The insulator protein CTCF is essential for mediating chromatin loops and regulating gene expression. While it established that DNA methylation hinders binding, the impacts of this methylation-sensitive binding on architecture transcription are poorly defined. Here, we used a selective DNMT1 inhibitor to investigate characteristics functions ‘reactivated’ peaks resulting from global demethylation. We found reactivated preferentially form bodies interact with highly-looping partner located in...
The insulator protein CTCF is essential for mediating chromatin loops and regulating gene expression. While it established that DNA methylation hinders binding, the impacts of this methylation-sensitive binding on architecture transcription are poorly defined. Here, we used a selective DNMT1 inhibitor to investigate characteristics functions ‘reactivated’ peaks resulting from global demethylation. We found reactivated preferentially form bodies interact with highly-looping partner located in...
Abstract Cancer mutations in Polycomb Repressive Complex 2 (PRC2) drive aberrant epigenetic states. Although therapies inhibiting the PRC2 enzymatic component EZH2 are FDA-approved, oncogene-specific dependencies remain to be discovered. Here, we identify that confer both resistance and drug addiction inhibitors EZH2-mutant lymphoma, resulting cancer cells paradoxically depend on for survival. Drug is mediated by hypermorphic CXC domain of EZH2, which maintain H3K27me3 levels even presence...
Abstract Drug addiction, a phenomenon where cancer cells paradoxically depend on continuous drug treatment for survival, has uncovered cell signaling mechanisms and co-dependencies. Here, we discover mutations that confer addiction to inhibitors of the transcriptional repressor Polycomb Repressive Complex 2 (PRC2) in diffuse large B-cell lymphoma (DLBCL). is mediated by hypermorphic CXC domain catalytic subunit EZH2, which maintain H3K27me3 levels even presence PRC2 inhibitors....