A5112631558- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- RNA modifications and cancer
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Cancer-related gene regulation
- Plant Taxonomy and Phylogenetics
- Cancer Genomics and Diagnostics
- Ubiquitin and proteasome pathways
- Microbial Metabolic Engineering and Bioproduction
- Genetics and Neurodevelopmental Disorders
- Redox biology and oxidative stress
- Enzyme Catalysis and Immobilization
- Immune Response and Inflammation
- Amino Acid Enzymes and Metabolism
- Neurological Disease Mechanisms and Treatments
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Gene expression and cancer classification
- Flavonoids in Medical Research
- Cell Adhesion Molecules Research
- Urinary Tract Infections Management
- Biofuel production and bioconversion
- Cancer Mechanisms and Therapy
- Motivation and Self-Concept in Sports
- Plant Molecular Biology Research
EpiCypher (United States)
2020-2025
Duke University
2015-2019
Link Institut (Switzerland)
2015
University of Miami
1983
Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized 'codes' are read by specialized regions (reader domains) chromatin-associated proteins (CAPs) to regulate downstream function. Substantial effort made define [CAP: histone PTM] specificities, and thus decipher the code guide epigenetic therapies. However, this largely done using reductive approach of isolated reader domains peptides, which cannot...
An age-related accumulation of D-aspartic acid was detected in the white matter ten normal brains from individuals aged 30 to 80 years. Gray showed no systematic increase acid. The rate constant for D-aspartate formation brain is equal predicted value calculated 37°C. Accumulation uncommon isomer myelinated implies that there little or turnover this tissue, and may have a bearing on dysfunction aging other diseases myelin.
Abstract Background Plant homeodomain (PHD) fingers are central “readers” of histone post-translational modifications (PTMs) with > 100 PHD finger-containing proteins encoded by the human genome. Many PHDs studied to date bind unmodified or methylated states H3 lysine 4 (H3K4). Additionally, many these domains, and they contained in, have crucial roles in regulation gene expression cancer development. Despite this, majority gone uncharacterized; thus, our understanding how domains...
In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact N-termini availability the epigenetic machinery. Notably, H3 tail acetylation (e.g. K9ac, K14ac, K18ac) linked increased H3K4me3 engagement by BPTF PHD finger, but it unknown if this mechanism has a broader extension. Here, we show that promotes nucleosomal accessibility other H3K4 methyl readers, importantly, extends writers,...
Histone H2A lysine 119 (H2AK119Ub) is monoubiquitinated by Polycomb repressive complex 1 and deubiquitinated deubiquitinase (PR-DUB). PR-DUB cleaves H2AK119Ub to restrict focal at target sites protect active genes from aberrant silencing. The subunits (BAP1 ASXL1) are among the most frequently mutated epigenetic factors in human cancers. How establishes specificity for over other nucleosomal ubiquitination how disease-associated mutations of enzyme affect activity unclear. Here, we determine...
Mutations in the
ABSTRACT Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized ‘codes’ are read by specialized regions (reader domains) associated proteins (CAPs) to regulate downstream function. Substantial effort made define [CAP-histone PTM] specificity, and thus decipher the histone code / guide epigenetic therapies. However, this largely done using reductive approach of isolated reader domains peptides, with...
Abstract Localized DNA methylation (DNAme), particularly 5-methylcytosine (5mC), contributes to the regulation of gene expression, imprinting, and silencing parasitic elements, with dysregulation implicated in multiple diseases including cancer. Understanding how DNAme signaling drives physiological dysfunction has great potential reveal novel biomarkers for therapeutic strategies. Despite growing evidence that is functionally linked various histone post translational modifications (PTMs),...
DNA methylation (DNAme) is a class of epigenetic marks that includes the cytosine residues (5mC) within CpG islands. In addition to well characterized roles regulating gene expression, imprinting, and silencing parasitic elements, misregulation DNAme implicated in multiple cancers. Evidence emerging not an independent mark but rather closely linked chromatin proteins. However, examining relationships between proteins hampered by correlative analyses cannot establish direct mechanistic link....
Chromatin is more than a simple genome packaging system, and instead locally distinguished by histone post-translational modifications (PTMs) that can directly change nucleosome structure / or be ″read″ chromatin-associated proteins to mediate downstream events. An accurate understanding of PTM binding preference vital explain normal function pathogenesis, has revealed multiple therapeutic opportunities. Such studies most often use peptides, even though these cannot represent the full...
Histone post-translational modifications (PTMs) often serve as distinct recognition sites for the recruitment of chromatin-associated proteins (CAPs) epigenome regulation. While CAP-PTM interactions have been extensively studied using histone peptides, this cannot consider regulatory potential multi-site binding on intact nucleosomes. To overcome limitation, we applied Nucleosome Mass Spectrometry (Nuc-MS), a native Top-Down MS approach that enables controlled disassembly CAP:nucleosome...
Lysine-specific demethylase 1A (KDM1A/LSD1) is a FAD-dependent enzyme that catalyzes the oxidative demethylation of histone H3K4me1/2 and H3K9me1/2 repressing activating transcription, respectively. Although active site expanded compared to members greater amine oxidase superfamily, it too sterically restricted encompass minimal 21-mer peptide substrate footprint. The remainder substrate/product therefore expected extend along surface KDM1A. We show full-length H3, which lacks any...
Abstract The maintenance of gene expression patterns during metazoan development is achieved by the actions Polycomb group (PcG) complexes. An essential modification marking silenced genes monoubiquitination histone H2A lysine 119 (H2AK119Ub) deposited E3 ubiquitin ligase activity non-canonical Repressive Complex 1. Deubiquitinase (PR-DUB) complex cleaves monoubiquitin from to restrict focal H2AK119Ub at target sites and protect active aberrant silencing. BAP1 ASXL1, subunits that form...
ABSTRACT In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact N-termini availability the epigenetic machinery. Notably, H3 tail acetylation ( e.g. , K9ac, K14ac, K18ac) linked increased H3K4me3 engagement by BPTF PHD finger, but it unknown if this mechanism has broader extension. Here we show that promotes nucleosomal accessibility other H3K4 methyl readers, importantly, extends...
A target with therapeutic potential, lysine‐specific demethylase 1A (KDM1A) is a regulator of gene expression whose tower domain protein–protein interaction motif. This facilitates the KDM1A coregulators and multiprotein complexes that direct its activity to nucleosomes. We describe design characterization chimeric ‘towerless’ KDM1A, termed nΔ150 KDM1AΔTower KDM1B chimera (chKDM1AΔTower), which incorporates region from paralog 1B (KDM1B). copurifies FAD displays activity, but fails bind...
CPAF (chlamydial protease-like activity factor) is a Chlamydia trachomatis protease that translocated into the host cytosol during infection. results in dampened inflammation signaling, cytoskeletal remodeling, and suppressed neutrophil activation. Although an emerging antivirulence target, its catalytic mechanism has been unexplored to date. Steady state kinetic parameters were obtained for recombinant with vimentin-derived peptide substrates using high-performance liquid...
Abstract Gene transcription is regulated by the complex interplay between histone post-translational modifications (PTMs), chromatin associated proteins (CAPs), and DNA methylation (DNAme). Mapping their genomic locations examining relationships these elements a powerful approach to decipher mechanisms of disease, thereby enabling discovery novel biomarkers therapeutics. Leading epigenomic mapping technologies (e.g., ChIP-seq, CUT&RUN) rely upon fragmentation isolate regions interest for...
Abstract DNA methylation (DNAme) is an epigenetic mark that includes the modification of cytosine resides (5mC) within CpG islands. In addition to well characterized roles regulating gene expression, imprinting and silencing parasitic elements, misregulation DNAme implicated in multiple diseases. Evidence emerging not independent but rather closely linked post translational (PTM) histone proteins. However, examining relationship between 5mC PTMs are hampered by usual approach analyses cannot...
Abstract Nuc-MS characterizes histone modifications and variants directly from intact endogenous nucleosomes. Preserving whole nucleosome particles enables precise interrogation of their protein content, as for H3.3-containing nucleosomes which had 6-fold co-enrichment variant H2A.Z over bulk chromatin. Nuc-MS, validated by ChIP-seq, showed co-occurrence oncogenic H3.3K27M with euchromatic marks (e.g., H4K16ac >15-fold enrichment H3K79me2). By capturing the entire epigenetic landscape,...
Abstract Chromatin remodeling is mediated by ATP-dependent enzymes that play key roles regulating gene expression and genome replication/repair. Aberrant nucleosome organization from dysregulated chromatin can severely alter accessibility disrupt these important processes, thereby driving various cancers. Remarkably, nearly 20% of all human cancers contain mutations in subunits the SWI/SNF family complexes, making them great interest to basic research therapeutic intervention. In vitro...