A5070893774- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- RNA Research and Splicing
- RNA modifications and cancer
- Protein Degradation and Inhibitors
- CRISPR and Genetic Engineering
- Acute Myeloid Leukemia Research
- RNA and protein synthesis mechanisms
- HIV Research and Treatment
- RNA regulation and disease
- Evolution and Genetic Dynamics
- Genetics and Neurodevelopmental Disorders
- Genetic Syndromes and Imprinting
- Advanced biosensing and bioanalysis techniques
- Cancer-related gene regulation
- Bone health and treatments
- DNA Repair Mechanisms
- Viral-associated cancers and disorders
- Mathematical and Theoretical Epidemiology and Ecology Models
- Telomeres, Telomerase, and Senescence
- Bacteriophages and microbial interactions
- Endoplasmic Reticulum Stress and Disease
- Chemical Synthesis and Analysis
Harvard University
2022-2025
Broad Institute
2022-2025
Harvard University Press
2024
National University Cancer Institute, Singapore
2010-2020
National University of Singapore
2010-2020
Yale University
2019-2020
Agency for Science, Technology and Research
2014
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,...
Adenosine-to-inosine (A-to-I) RNA editing entails the enzymatic deamination of adenosines to inosines by adenosine deaminases acting on (ADARs). Dysregulated A-to-I has been implicated in various diseases, including cancers. However, precise factors governing and their physiopathological implications remain as a long-standing question. Herein, we unravel that DEAH box helicase 9 (DHX9), at least partially dependent its activity, functions bidirectional regulator cancer cells. Intriguingly,...
Allostery enables dynamic control of protein function. A paradigmatic example is the tightly orchestrated process DNA methylation maintenance. Despite fundamental importance allosteric sites, their identification remains highly challenging. Here, we perform CRISPR scanning on essential maintenance machinery—DNMT1 and its partner UHRF1—with activity-based inhibitor decitabine to uncover mechanisms regulating DNMT1. In contrast non-covalent DNMT1 inhibition, selection implicates numerous...
Abstract Introduction Metastatic breast cancer cells frequently and ectopically express the transcription factor RUNX2, which normally attenuates proliferation promotes maturation of osteoblasts. RUNX2 expression is inversely regulated with respect to cell growth in osteoblasts deregulated osteosarcoma cells. Methods Here, we addressed whether functional relationship between gene maintained We also investigated aberrant linked phenotypic parameters that could provide a selective advantage...
Abstract CCAAT/enhancer-binding protein alpha (C/EBPα) is an essential transcription factor for myeloid lineage commitment. Here we demonstrate that acetylation of C/EBPα at lysine residues K298 and K302, mediated least in part by general control non-derepressible 5 (GCN5), impairs DNA-binding ability modulates transcriptional activity. Acetylated enriched human leukaemia cell lines acute (AML) samples, downregulated upon granulocyte-colony stimulating (G-CSF)- granulocytic differentiation...
Significance The therapeutic use of drugs against microbial pathogens and cancer is currently undergoing a paradigm shift from traditional therapies toward adaptive therapies, which attempt to minimize the risk evolution drug resistance. Adaptive treat with short bouts application followed by periods without treatment allow resistant cells be naturally outcompeted susceptible cells. However, fitness cost resistance frequently too small for rapidly cells, compromising effectiveness future...
Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function 1 . As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma (MB) 2 , most common embryonal brain tumor children, and pineoblastoma 3 These impart gain-of-function induce degradation transcriptional corepressor CoREST 4 However, their mechanism action remains unresolved. Here, we elucidate mechanistic basis by which promote through...
HIV1-TAT interactive protein (TIP60) is a haploinsufficient tumor suppressor. However, the potential mechanisms endowing its suppressor ability remain incompletely understood. It plays vital role in virus-induced cancers where TIP60 down-regulates expression of human papillomavirus (HPV) oncoprotein E6 which turn destabilizes TIP60. This intrigued us to identify TIP60, context viral infection, it targeted by oncoproteins. Through an array molecular biology techniques such as Chromatin...
A wide range of noncanonical amino acids (ncAAs) can be incorporated into proteins in living cells by using engineered aminoacyl-tRNA synthetase/tRNA pairs. However, most tRNA synthetases are polyspecific; that is, they recognize multiple rather than one ncAA. Polyspecificity imposes a limit to the use genetic code expansion because it prevents specific incorporation desired ncAA when ncAAs present growth media. In this study, we employed directed evolution improve substrate selectivity...
Acute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has worst prognosis among all subtypes of MLL-rearranged AMLs. is expressed solely and its regulated directly MLL-AF6/DOT1L. Suppression induces robust apoptosis human AML cells. Genetic deletion mice delays development leukemia attenuated...
// Qiao Jing Lew 1,* , Kai Ling Chu Yi Chia 1 Benjamin Soo Jia Pei Ho Chew Har Ng Hui Si Kwok Cheng-Ming Chiang 2 Yao Chang 3 and Sheng-Hao Chao 1,4 Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Research (A*STAR), Singapore Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Harry Hines Boulevard, Dallas, TX, USA National Institute Infectious Diseases Vaccinology, Health Institutes, Tainan, Taiwan 4 Department Microbiology,...
A bstract Eukaryotic cells are divided into the nucleus and cytosol, and, to enter nucleus, proteins typically possess short signal sequences, known as nuclear localization signals (NLSs). Although NLSs have long been considered features unique eukaryotic proteins, we show here that similar or identical protein segments present in ribosomal from Archaea. Specifically, uL3, uL15, uL18, uS12 NLS-type motifs conserved across all major branches of Archaea, including most ancient groups...
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...
Genome editing enables sequence-function profiling of endogenous cis-regulatory elements, driving understanding their mechanisms and the development gene therapies. However, these approaches cannot be combined with direct scalable readouts chromatin structure accessibility across long single-molecule fibers. Here we leverage a double-stranded DNA cytosine deaminase to profile at high depth resolution loci interest through targeted PCR long-read sequencing, method term deaminase-accessible...
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....
ABSTRACT Antibiotic resistance frequently evolves through fitness trade-offs in which the genetic alterations that confer to a drug can also cause growth defects resistant cells. Here, experimental evolution microfluidics-based turbidostat, we demonstrate antibiotic-resistant cells be efficiently inhibited by amplifying costs associated with drug-resistance evolution. Using tavaborole-resistant E. coli as model, show mutations leucyl-tRNA synthetase (that underlie tavaborole resistance) make...