A5067188352- Genomics and Chromatin Dynamics
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- RNA and protein synthesis mechanisms
- Chromatin Remodeling and Cancer
- RNA modifications and cancer
- Plant Molecular Biology Research
- Histone Deacetylase Inhibitors Research
- Ubiquitin and proteasome pathways
- Protein Structure and Dynamics
- RNA Research and Splicing
- DNA and Nucleic Acid Chemistry
- Advanced biosensing and bioanalysis techniques
- Signaling Pathways in Disease
- Cancer Mechanisms and Therapy
- Chemical Synthesis and Analysis
- Lipid Membrane Structure and Behavior
- Chromosomal and Genetic Variations
- Cellular transport and secretion
- thermodynamics and calorimetric analyses
- Enterobacteriaceae and Cronobacter Research
- Molecular Biology Techniques and Applications
- Polyamine Metabolism and Applications
- Urinary Tract Infections Management
University of Colorado Anschutz Medical Campus
2014-2024
University of Iowa
2015-2024
University of Colorado Denver
2009-2024
University of Michigan–Ann Arbor
2006-2009
University of Colorado Health
2008
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...
A major challenge in chromatin biology is to understand the mechanisms by which remodeled into active or inactive states as required during development and cell differentiation. One complex implicated these processes nucleosome remodeling histone deacetylase (NuRD) complex, contains both activities has been silencing of subsets genes involved various stages cellular development. Chromodomain-helicase-DNA-binding protein 4 (CHD4) a core component NuRD ATPase domain along with two...
Histone tails harbor a plethora of post-translational modifications that direct the function chromatin regulators, which recognize them through effector domains. Effector domain/histone interactions have been broadly studied, but largely using peptide fragments histone tails. Here, we extend these studies into nucleosome context and find conformation adopted by H3 is inhibitory to BPTF PHD finger binding. Using NMR spectroscopy MD simulations, show interact robustly dynamically with...
CHD4 is a catalytic subunit of the NuRD (nucleosome remodeling and deacetylase) complex essential in transcriptional regulation, chromatin assembly DNA damage repair. contains tandem plant homeodomain (PHD) fingers connected by short linker, biological function which remains unclear. Here we explore combinatorial action PHD1/2 detail molecular basis for their association with chromatin. We found that targets nucleosomes multivalent manner, concomitantly engaging two histone H3 tails. This...
Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. After cardiac stress, JP2 cleaved by the calcium ion-dependent protease calpain, which disrupts E-C coupling ultrastructural machinery and drives heart failure progression. We found that stress-induced proteolysis of liberates an N-terminal fragment (JP2NT) translocates to nucleus, binds genomic DNA, controls expression spectrum genes in cardiomyocytes. Transgenic overexpression JP2NT mice...
CHD4 (chromodomain helicase DNA-binding protein 4) ATPase is a major subunit of the repressive NuRD (nucleosome remodelling and deacetylase) complex, which involved in transcriptional regulation development. contains two PHD (plant homeodomain) fingers unknown function. Here we show that second finger (PHD2) recognizes N-terminus histone H3 this interaction facilitated by acetylation or methylation Lys9 (H3K9ac H3K9me respectively) but inhibited Lys4 (H3K4me) Ala1 (H3A1ac). An 18 μM binding...
Combinatorial polyvalent contacts of histone-binding domains or readers commonly mediate localization and activities chromatin-associated proteins. A pair readers, the PHD fingers protein CHD4, has been shown to bivalently recognize histone H3 tails. Here we describe a mechanism by which these linked but independent bind intact nucleosome core particle (NCP). Comprehensive NMR, chemical reactivity, molecular dynamics, fluorescence analyses point critical roles intra-nucleosomal histone-DNA...
BRG1 and BRM, central components of the BAF (mSWI/SNF) chromatin remodelling complex, are critical in structure regulation. Here, we show that human BRM (hBRM) bromodomain (BRD) has moderate specificity for H3K14ac. Surprisingly, also find both hBRM BRDs have DNA-binding activity. We demonstrate associate with DNA through a surface basic patch BRD an adjacent AT-hook make multivalent contacts DNA, leading to robust affinity AT-rich elements. Although can bind H3K14ac simultaneously,...
Polycomb repressive complex 1 (PRC1) is critical for mediating gene expression during development. Five chromobox (CBX) homolog proteins, CBX2, CBX4, CBX6, CBX7, and CBX8, are incorporated into PRC1 complexes, where they mediate targeting to trimethylated lysine 27 of histone H3 (H3K27me3) via the N-terminal chromodomain (ChD). Individual CBX paralogs have been implicated as drug targets in cancer; however, high similarities sequence structure among ChDs provide a major obstacle developing...
Hexasomes and tetrasomes are intermediates in nucleosome assembly disassembly. Their formation is promoted by histone chaperones, ATP-dependent remodelers, RNA polymerase II. In addition, hexasomes maintained transcribed genes could be an important regulatory factor. While composition has been shown to affect the structure accessibility of DNA, its influence on tails largely unknown. Here, we investigate conformational dynamics H3 tail hexasome tetrasome. Using a combination NMR...
Polyamines are polycationic alkyl-amines abundant in proliferating stem and cancer cells. How these metabolites influence numerous cellular functions remains unclear. Here we show that polyamine levels decrease during differentiation inhibiting synthesis leads to a differentiated-like cell state. concentrate the nucleus further enriched nucleoli of cells culture
Abstract The FYVE domain associates with phosphatidylinositol 3‐phosphate [PtdIns(3)P] in membranes of early endosomes and penetrates bilayers. Here, we detail principles membrane anchoring show that the insertion into PtdIns(3)P‐enriched membrane‐mimetics is substantially increased acidic conditions. EEA1 binds to POPC/POPE/PtdIns(3)P vesicles a Kd 49 nM at pH 6.0, however ∼24 fold weaker 8.0. decrease affinity primarily due much faster dissociation protein from bilayers basic media....