A5003540301- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Cancer-related gene regulation
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Advanced Glycation End Products research
- RNA and protein synthesis mechanisms
- Protein Degradation and Inhibitors
- RNA Interference and Gene Delivery
- Click Chemistry and Applications
- Peroxisome Proliferator-Activated Receptors
- Hepatitis B Virus Studies
- Histone Deacetylase Inhibitors Research
- Cancer, Hypoxia, and Metabolism
- Cancer-related Molecular Pathways
- Cancer Genomics and Diagnostics
- Advanced biosensing and bioanalysis techniques
- Metabolism, Diabetes, and Cancer
- Single-cell and spatial transcriptomics
- HIV Research and Treatment
- Erythrocyte Function and Pathophysiology
- Hepatitis C virus research
- Immune Cell Function and Interaction
- Glycosylation and Glycoproteins Research
Cornell University
2018-2025
Tri-Institutional PhD Program in Chemical Biology
2018-2025
Memorial Sloan Kettering Cancer Center
2017-2025
Weill Cornell Medicine
2019-2024
Kettering University
2020-2024
New York Proton Center
2023
Child Trends
2021-2022
Princeton University
2014-2021
Weizmann Institute of Science
2010-2015
Abstract Cellular proteins continuously undergo non-enzymatic covalent modifications (NECMs) that accumulate under normal physiological conditions and are stimulated by changes in the cellular microenvironment. Glycation, hallmark of diabetes, is a prevalent NECM associated with an array pathologies. Histone particularly susceptible to NECMs due their long half-lives nucleophilic disordered tails extensive regulatory modifications; however, histone remain poorly understood. Here we perform...
Abstract Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced metastatic cancers 1–4 , but whether they mechanistically linked is unknown. Here we show that missegregation mitotic chromosomes, their sequestration in micronuclei 5,6 subsequent rupture the micronuclear envelope 7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans mice, as well cancer non-transformed cells. Some changes PTMs occur...
Abstract Histone H3 monoaminylations at Gln5 represent an important family of epigenetic marks in brain that have critical roles permissive gene expression 1–3 . We previously demonstrated serotonylation 4–10 and dopaminylation 9,11–13 histone (H3Q5ser H3Q5dop, respectively) are catalysed by transglutaminase 2 (TG2), alter both local global chromatin states. Here we found TG2 additionally functions as eraser exchanger monoaminylations, including H3Q5 histaminylation (H3Q5his), which displays...
The ubiquitin-proteasome pathway plays a crucial role in many cellular processes by degrading substrates tagged polyubiquitin chains, linked mostly through lysine 48 of ubiquitin. Although polymerization ubiquitin via its six other residues exists vivo as part various physiological pathways, the molecular mechanisms that determine type chains remained largely unknown. We undertook systematic, vitro, approach to evaluate E2 enzymes determining topology polyubiquitin. Because this study was...
Abstract Biomolecular condensation constitutes an emerging mechanism for transcriptional regulation. Recent studies suggest that the co-condensation between transcription factors (TFs) and DNA can generate mechanical forces driving genome rearrangements. However, reported generated by protein-DNA are typically below one piconewton (pN), questioning its physiological significance. Moreover, force-generating capacity of these condensates in chromatin context remains unknown. Here, we show...
Ubiquitin-conjugating enzymes (E2s) have a dominant role in determining which of the seven lysine residues ubiquitin is used for polyubiquitination. Here we show that tethering substrate to an E2 enzyme absence E3 ligase sufficient promote its ubiquitination, whereas type conjugates and identity target on are promiscuous. In contrast, when introduced, clear decision between mono- polyubiquitination made, conjugation as well residue becomes highly specific. These features can be further...
Significance This article applies a range of protein ligation methods at the level chromatin to understand cross-talk mechanism between well-established biomedical target human Dot1 (hDot1L) methyltransferase and ubiquitylation H2B lysine 120. Through systematic structure–activity relationship study ubiquitin surface in regard hDot1L-mediated H3K79 methylation further investigation with precisely engineered substrates, functional hotspot within was identified that is essential stimulation...
Abstract Protein arginine deiminase 4 (PAD4) facilitates the post-translational citrullination of core histones H3 and H4. While precise epigenetic function this modification has not been resolved, it shown to associate with general chromatin decompaction compete methylation. Recently, we found that are subjected methylglyoxal (MGO)-induced glycation on nucleophilic side chains, particularly arginines, under metabolic stress conditions. These non-enzymatic adducts change architecture...
DOT1L, the only H3K79 methyltransferase in human cells and a homolog of yeast Dot1, normally forms complex with AF10, AF17, ENL or AF9, is dysregulated most cases mixed-lineage leukemia (MLLr), has been believed to regulate transcriptional elongation on basis its colocalization RNA polymerase II (Pol II), sharing subunits (AF9 ENL) between DOT1L super complexes, distribution methylation both promoters transcribed regions active genes. Here we show that depletion erythroleukemic reduces...
Because of their long half-lives and highly nucleophilic tails, histones are particularly susceptible to accumulating nonenzymatic covalent modifications, such as glycation. The resulting modifications can have profound effects on cellular physiology due the regulatory role play in all DNA-templated processes; however, complexity Maillard chemistry proteins makes tracking enriching for glycated a challenging task. Here, we characterize glyoxal (GO) using quantitative proteomics an...
Abstract Glycation, a non-enzymatic post-translational modification occurring on proteins, can be actively reversed via site-specific phosphorylation of the fructose-lysine moiety by FN3K kinase, to impact cellular function target protein. A regulatory axis between and glycated protein targets has been associated with conditions like diabetes cancer. However, molecular basis this relationship not explored so far. Here, we determined series crystal structures HsFN3K in apo-state, complex...
Significance Programmable DNA-binding proteins such as nuclease-deficient Cas9 (dCas9) offer a simple system for genomic localization of genetically encodable biomolecules. These tools have enabled characterization numerous different chromatin effectors at specific genetic elements. The delivery fully synthetic cargos to loci is currently limited by lack adequate technologies. Here we used protein trans -splicing ligate chemical moieties dCas9 in vitro and subsequently deliver these...