A5005884580- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Histone Deacetylase Inhibitors Research
- Multiple Myeloma Research and Treatments
- Microtubule and mitosis dynamics
- CAR-T cell therapy research
- Chromatin Remodeling and Cancer
- Cancer, Hypoxia, and Metabolism
- Acute Myeloid Leukemia Research
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- Cancer-related Molecular Pathways
- Adipose Tissue and Metabolism
- Sirtuins and Resveratrol in Medicine
- Peptidase Inhibition and Analysis
- Neuroblastoma Research and Treatments
- Immune Cell Function and Interaction
- Immune cells in cancer
- RNA Research and Splicing
- Acute Lymphoblastic Leukemia research
- Genomics and Chromatin Dynamics
- Cardiac Fibrosis and Remodeling
- Congenital heart defects research
- Cancer Treatment and Pharmacology
- T-cell and B-cell Immunology
Planta
2024
Kingston General Hospital
2015-2019
Queen's University
2016
Dana-Farber Cancer Institute
2007-2013
Harvard University
2008-2013
Boston Children's Hospital
2013
Institut pour l'avancée des biosciences
2011
Brigham and Women's Hospital
2011
Université Joseph Fourier
2011
Université Grenoble Alpes
2011
Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between pathway has been reported. Here we investigate such mammals. We show Sirt1 positively regulates insulin secretion pancreatic beta cells. represses uncoupling protein (UCP) gene UCP2 by binding directly to promoter. cell lines which is reduced SiRNA, levels elevated blunted. The up-regulation of associated with failure cells increase ATP after...
The yeast Sir2p protein has an essential role in maintaining telomeric and mating type genes their transcriptionally inactive state. Mammalian cells have a very large proportion of genome also contain seven that regions homology with the sir2 gene. One these mammalian genes, sir2alpha, is presumptive homologue We set out to determine if sir2alpha plays gene silencing by creating strain mice carrying null allele sir2alpha. Animals two alleles were smaller than normal at birth, most died...
Adaptation to hypoxia is mediated through a coordinated transcriptional response driven largely by hypoxia-inducible factor 1 (HIF-1). We used ChIP-chip and gene expression profiling identify direct targets of HIF-1 transactivation on genome-wide scale. Several hundred were identified and, as expected, highly enriched for proteins that facilitate metabolic adaptation hypoxia. Surprisingly, there was also striking enrichment the family 2-oxoglutarate dioxygenases, including jumonji-domain...
A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of selective small-molecule inhibitor (JQ1) bromodomain and extraterminal (BET) subfamily epigenetic reader proteins. Here, report potent inhibition testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical crystallographic studies confirm that occupancy BRDT acetyl-lysine binding pocket by...
How T cells maintain their identity Although best known for pathogen-fighting prowess, lymphocytes also ensure that the immune response does not run amok. A subset of called regulatory (T regs ) performs this function by, example, making sure only attack pathogens and self. can exhibit plasticity in functions face an inflammatory stimulus. Kim et al. sought to identify molecules stable maintenance . Using genetically modified mice, they found both CD4 + CD8 require transcription factor...
Abstract Canonical roles for macrophages in mediating the fibrotic response after a heart attack include extracellular matrix turnover and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal that directly contribute forming post-injury scar. Unbiased transcriptomics shows an upregulation collagens both zebrafish mouse following injury. Adoptive transfer macrophages, from either collagen-tagged or adult GFP tpz -collagen donors, enhances scar formation via cell...
Despite current standard of care, the average 5-year mortality after an initial diagnosis heart failure (HF) is about 40%, reflecting urgent need for new therapeutic approaches. Previous studies demonstrated that epigenetic reader protein bromodomain-containing 4 (BRD4), emerging target in cancer, functions as a critical coactivator pathologic gene transactivation during cardiomyocyte hypertrophy. However, relevance these findings to human disease remained unknown. We demonstrate treatment...
Blocking BCL9/β-catenin interaction with a stapled peptide inhibits Wnt-dependent transcription and suppresses growth metastasis in colon cancer multiple myeloma.
Abstract NUT midline carcinoma (NMC) is an aggressive subtype of squamous cell that typically harbors BRD4/3–NUT fusion oncoproteins block differentiation and maintain tumor growth. In 20% cases, fused to uncharacterized non-BRD gene(s). We established a new patient-derived NMC line (1221) demonstrated it novel NSD3–NUT oncogene. find both necessary sufficient for the blockade maintenance proliferation in cells. binds BRD4, BRD bromodomain inhibitors induce arrest 1221 further NSD3 required...
NUT midline carcinoma (NMC) is a lethal pediatric tumor defined by the presence of BRD-NUT fusion proteins that arrest differentiation. Here we explore mechanisms underlying ability BRD4-NUT to prevent squamous In both gain-of and loss-of-expression assays, find expression associated with globally decreased histone acetylation transcriptional repression. Bulk chromatin can be restored treatment NMC cells deacetylase inhibitors (HDACi), engaging program differentiation arrested growth in...
Spindle oscillations are commonly observed during stage 2 of non-rapid eye movement sleep. During sleep spindles, the cerebral cortex and thalamus interact through feedback connections. Both initiation termination spindle thought to originate in based on thalamic recordings computational models, although some <i>in vivo</i> results suggest otherwise. Here, we have used computer modeling multisite from cats examine involvement oscillations. We found that propagation spindles depended synaptic...
Numerous lines of study have suggested that the Hox genes, encoding putative transcription factors, are key genes in establishment body plan mammalian embryo. To examine role Hoxa-5 (Hox1.3) gene during development, we used targeted mutagenesis embryonic stem cells to produce a strain mice carrying disrupted allele. The viability homozygous mutant is markedly reduced, with 50% animals dying at birth or shortly thereafter. Analysis skeleton mutants reveals number homeotic transformations...
Rationale: Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in preclinical models heart failure (HF). However, since target ubiquitously, it is unclear whether this chromatin reader functions cell type-specific manner control pathological myocardial fibrosis. Furthermore, molecular mechanisms by which stimulates transcriptional program for remain unknown. Objective: We sought test hypothesis that a cell-autonomous and...
To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT midline carcinoma (NMC), we have identified protein interactions unique to BRD4-NUT fusion oncoprotein compared with wild-type BRD4. Using cross-linking, affinity purification, and mass spectrometry, EP300 acetyltransferase as uniquely associated BRD4 through both NMC non-NMC cell types. We also discovered ZNF532 patient cells but not detectable 293T cells. are implicated feed-forward regulatory loops...
Recent studies have identified a genetic variant rs641738 near two genes encoding membrane bound O -acyltransferase domain-containing 7 ( MBOAT7 ) and transmembrane channel-like 4 TMC4 that associate with increased risk of non-alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), alcohol-related cirrhosis, fibrosis in those infected viral hepatitis (Buch et al., 2015; Mancina 2016; Luukkonen Thabet Viitasalo Krawczyk 2017; 2017). Based on hepatic expression quantitative trait loci...
Although Astyanax mexicanus surface fish regenerate their hearts after injury, Pachón cave-dwelling counterparts cannot and, instead, form a permanent fibrotic scar, similar to the human heart. Myocardial proliferation peaks at levels in both and 1 week injury. However, Pachón, this peak coincides with strong scarring immune response, ultimately, cavefish cardiomyocytes fail replace scar. We identified lrrc10 be upregulated compared Similar cavefish, knockout of zebrafish impairs heart...
Background: Cardiovascular risk in diabetes remains elevated despite glucose-lowering therapies. We hypothesized that hyperglycemia induces trained immunity macrophages, promoting persistent proatherogenic characteristics. Methods: Bone marrow–derived macrophages from control mice and with were grown physiological glucose (5 mmol/L) subjected to RNA sequencing (n=6), assay for transposase accessible chromatin immunoprecipitation (n=6) determination of hyperglycemia-induced immunity. marrow...
Identifying the genetic factors that underlie complex traits is central to understanding mechanistic underpinnings of evolution. Cave-dwelling Astyanax mexicanus populations are well adapted subterranean life and many appear have evolved troglomorphic independently, while surface-dwelling can be used as a proxy for ancestral form. Here we present high-resolution, chromosome-level surface fish genome, enabling first genome-wide comparison between cavefish populations. Using this resource,...