R35GM139569

Function of Protein Methylation in Chromatin and Signaling Regulation - Abstract

Covalent post-translational protein modifications (PTMs) contribute to all aspects of cell physiology and are a major source of protein functional diversity in mammalian cells. Aberrant regulation of PTMs is a common feature of human diseases. Our research focuses on two important PTMs: protein methylation at lysine and histidine residues. Our overarching goal is to elucidate at a molecular level the physiologic roles for lysine and histidine methylation signaling in the regulation of chromatin biology, epigenetics, and other fundamental biological processes, and to understand how disruption in these mechanisms contributes to human disease.

Within this research framework, we will investigate the biology and function of enzymes that regulate histone methylation dynamics, with a focus on methylation at histone H3 lysine 36 (H3K36). Beyond histone methylation, there is a growing appreciation that a number of non-histone proteins, including several with clear roles in gene expression and signal transduction, are lysine methylated. Indeed, there are likely far greater than one hundred lysine methyltransferases in the human genome, and an increasing number of examples of mutation or translocation of these genes being linked to human disorders. Thus, it is likely that deregulation in non-histone protein methylation homeostasis plays a crucial role in disease pathogenesis. We will explore the biology and function of new enzymes and non-histone protein methylation signaling pathways.

In addition to lysine methylation, other residues like histidine are also methylated; though relatively little is known about the histidine methylation modification network. We will explore the hypothesis that protein histidine methylation has an underappreciated and significant role in signal transduction, cell biology, and disease pathogenesis. For our studies, we will use a multi-disciplinary strategy that includes biochemical, molecular, proteomic, genomic, cellular, and mouse modeling approaches.

The Leland Stanford Junior University

THE NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES (NIGMS) SUPPORTS BASIC RESEARCH THAT INCREASES OUR UNDERSTANDING OF BIOLOGICAL PROCESSES AND LAYS THE FOUNDATION FOR ADVANCES IN DISEASE DIAGNOSIS, TREATMENT, AND PREVENTION. NIGMS ALSO SUPPORTS RESEARCH IN SPECIFIC CLINICAL AREAS THAT AFFECT MULTIPLE ORGAN SYSTEMS: ANESTHESIOLOGY AND PERI-OPERATIVE PAIN, CLINICAL PHARMACOLOGY ?COMMON TO MULTIPLE DRUGS AND TREATMENTS, AND INJURY, CRITICAL ILLNESS, SEPSIS, AND WOUND HEALING.? NIGMS-FUNDED SCIENTISTS INVESTIGATE HOW LIVING SYSTEMS WORK AT A RANGE OF LEVELSFROM MOLECULES AND CELLS TO TISSUES AND ORGANSIN RESEARCH ORGANISMS, HUMANS, AND POPULATIONS. ADDITIONALLY, TO ENSURE THE VITALITY AND CONTINUED PRODUCTIVITY OF THE RESEARCH ENTERPRISE, NIGMS PROVIDES LEADERSHIP IN SUPPORTING THE TRAINING OF THE NEXT GENERATION OF SCIENTISTS, ENHANCING THE DIVERSITY OF THE SCIENTIFIC WORKFORCE, AND DEVELOPING RESEARCH CAPACITY THROUGHOUT THE COUNTRY.

93.859 - Biomedical Research and Research Training

National Institute of General Medical Sciences (NIGMS) [HHS - NIH]

Stanford, California 94305 United States

Single Zip Code

Maximizing Investigators' Research Award (R35 - Clinical Trial Optional) (PAR-19-367)

Amendment Since initial award the total obligations have increased 425% from $627,416 to $3,296,868.