A5004377642- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Telomeres, Telomerase, and Senescence
- interferon and immune responses
- Ubiquitin and proteasome pathways
- CRISPR and Genetic Engineering
- Cancer-related gene regulation
- Immune cells in cancer
- DNA Repair Mechanisms
- Liver Disease Diagnosis and Treatment
- Retinoids in leukemia and cellular processes
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Peptidase Inhibition and Analysis
- Genetics, Aging, and Longevity in Model Organisms
- Redox biology and oxidative stress
- Infection Control in Healthcare
- Atherosclerosis and Cardiovascular Diseases
- Cytokine Signaling Pathways and Interactions
- Metabolomics and Mass Spectrometry Studies
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Intergenerational Family Dynamics and Caregiving
- Health, Environment, Cognitive Aging
- Adipose Tissue and Metabolism
Discovery Institute
2018-2025
Sanford Burnham Prebys Medical Discovery Institute
2018-2025
Epigenomics (Germany)
2023-2025
University of Arizona
2012-2023
La Jolla Alcohol Research
2023
Shanghai Institute for Science of Science
2023
Weatherford College
2023
Torrey Pines Institute For Molecular Studies
2023
Cellular senescence is a stable form of cell cycle arrest associated with proinflammatory responses. Senescent cells can be cleared by the immune system as part normal tissue homeostasis. However, senescent also accumulate in aged and diseased tissues, contributing to inflammation disease progression. The mechanisms mediating impaired immune-mediated clearance are poorly understood. Here, we report that upregulate checkpoint molecule PD-L1, ligand for PD-1 on cells, which drives...
The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation primary conjugated and secondary bile acids (BAs) are features human hepatocellular carcinoma experimental liver models. Inhibiting BA synthesis hepatocytes through deletion BA-conjugating enzyme acid–CoA:amino acid N -acyltransferase (BAAT) enhanced tumor-specific T cell...
Inanimate surfaces, or fomites, can serve as routes of transmission enteric and respiratory pathogens. No previous studies have evaluated the impact surface disinfection on level pathogen transfer from fomites to fingers. Thus, present study investigated change in microbial contaminated fingers following disinfecting wipe use. Escherichia coli (10(8) 10(9) CFU/ml), Staphylococcus aureus (10(9) Bacillus thuringiensis spores (10(7) 10(8) poliovirus 1 PFU/ml) were seeded ceramic tile, laminate,...
Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with variety of other drugs. However, rational selection companion HDACi difficult due to their poorly-understood, cell-type specific mechanisms action. To address this, we developed pre-clinical model system sensitivity and...
Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic in senescent cells through mitochondria-regulated molecular circuit involving p53 cytoplasmic chromatin fragments (CCF) that enriched for DNA damage signaling marker γH2A.X. We show suppresses CCF accumulation its downstream inflammatory phenotype. activation formation linked to enhanced repair genome integrity....
Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma. While the initial treatment strategy highly effective, relapse occurs in 40% cases. Histone deacetylase inhibitors (HDACi) are a promising class anti-cancer drugs but their single agent efficacy against relapsed DLBCL has been variable, ranging from few complete/partial responses to some stable disease. However, most patients showed no response HDACi monotherapy for unknown reasons. Here we show that...
Approved histone deacetylase (HDAC) inhibitors have low efficacy against the most commonly-diagnosed non-Hodgkin lymphoma, diffuse large B cell lymphoma (DLBCL), but mechanisms underlying clinical resistance are poorly understood. Using a DLBCL cell-based model, we previously demonstrated that to pan-HDAC (HDACi) is characterized by reversible growth arrest and sensitivity mitotic apoptosis. The goal of current study better define cytotoxic effects HDACi using HDAC-selective determine which...
Abstract METTL3 is the catalytic subunit of methyltransferase complex, which mediates m 6 A modification to regulate gene expression. In addition, regulates transcription in an enzymatic activity-independent manner by driving changes high-order chromatin structure. However, how these functions complex are coordinated remains unknown. Here we show that coordinates its activity-dependent and independent cellular senescence, a state stable cell growth arrest. Specifically, METTL3-mediated loops...
Summary Gene expression programs are regulated by enhancers which act in a context-specific manner, and can reside at great distances from their target genes. Extensive three-dimensional (3D) genome reorganization occurs senescence, but how enhancer interactomes reconfigured during this process is just beginning to be understood. Here we generated high-resolution contact maps of active genes, assessed chromatin accessibility, established one-dimensional various histone modifications...
<title>Abstract</title> Biomarkers of biological age that predict the risk disease and expected lifespan better than chronologi-cal are key to efficient cost-effective healthcare1–3. To advance a personalized approach healthcare, such biomarkers must reliably accurately capture individual biology, age, provide scalable measurements. We developed novel – image-based chromatin epigenetic (ImAge) captures intrinsic progressions which readily emerge as principal changes in spatial organization...
Abstract The incidence of liver cancer is increasing and there an urgent need for new therapies preventative strategies. Age a major risk factor cancer, the reasons which are not well defined. One hallmarks aging immune dysfunction affects homeostasis potentially making it prone to cancer. To understand role in liver, we analyzed cells from young old livers. As reported before, aged livers observed increase CD101+PD1+CD8+ T cell population as IFNγ+TNFα+ suggesting response liver. We next...
This is a mouse dissection protocol intended to collect the 5 organs outlined in SBPMDI TMC: Brain, Bone Marrow, Colon, Liver, and Mammary. Liver collected as whole liver opposed hepatocytes or perfused liver. Brain alternatively hippocampus hemisphere for OCT FFPE. marrow viable cells frozen down freezing media.
Abstract Age is a major risk factor for liver cancer, as the case most adult human cancers. However, underlying mechanisms are not well defined. A better understanding of role aging in and other cancers can facilitate approaches assessment, early detection prevention. We hypothesize that age-driven changes render aged more sensitive to oncogenic stress hence tumorigenesis. To investigate how with age, we documented immune profile, transcriptome epigenome healthy livers from both young mice,...
Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in epigenetic regulation of SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. identified mitochondrial carrier (SLC25A1) ATP-citrate lyase (ACLY) as critical this process. Inhibiting these pathways selectively suppresses without affecting...
<title>Abstract</title> Age is a major risk factor for liver cancer, as the case most adult human cancers. However, underlying mechanisms are not well defined. A better understanding of role aging in and other cancers can facilitate approaches assessment, early detection prevention. We hypothesize that age-driven changes render aged more sensitive to oncogenic stress hence tumorigenesis. To investigate how with age, we documented immune profile, transcriptome epigenome healthy livers from...
Cellular senescence, a stress-induced stable proliferation arrest associated with an inflammatory Senescence-Associated Secretory Phenotype (SASP), is cause of aging. In senescent cells, Cytoplasmic Chromatin Fragments (CCFs) activate SASP via the anti-viral cGAS/STING pathway. PML protein organizes nuclear bodies (NBs), also involved in senescence and immunity. The HIRA histone H3.3 chaperone localizes to NBs cells. Here, we show that are essential for expression, tightly linked HIRA's...
Abstract Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Understanding their interrelationship will help unravel new mechanisms therapeutic targets aging age-associated diseases. Here we report a novel mechanism directly linking genomic in senescent cells through mitochondria-regulated molecular circuit driven by p53 cytoplasmic chromatin fragments (CCF). We show, activation or inactivation genetic pharmacologic...
Abstract Patients diagnosed with Diffuse Large B-cell lymphoma have an overall 60% five-year survival rate. New therapeutic approaches are needed to effectively treat aggressive forms of DLBCL that refractory the standard treatment or relapse within two years treatment. Histone deacetylase inhibitors (HDACi) novel therapeutics well tolerated in humans and being extensively evaluated combination other against hematologic malignancies. Rational selection companion has been difficult due cell...