Outstanding Scientific Achievement Award winner advances understanding of epigenetics of type 2 diabetes predisposition
Genome-wide association studies (GWAS)—in which entire genomes of people with and without a disease or condition are queried for genetic variants—have helped identify type 2 diabetes susceptibility loci scattered throughout the human genome.
The next frontier in type 2 diabetes genomic research is to uncover how variants impact risk, pathogenesis, and progression of the disease and to translate these data into diabetes prevention and therapeutic strategies.
“Type 2 diabetes is consistently among the largest disease GWAS, showing that as a community, we are leaders,” said Stephen C.J. Parker, PhD, Associate Professor of Computational Medicine and Bioinformatics and Associate Professor of Human Genetics at the University of Michigan School of Medicine, the 2024 American Diabetes Association® (ADA) Outstanding Scientific Achievement Award winner.
Dr. Parker’s lecture, “Insulin and Instructions—How the Epigenome Directs Diabetes,” was presented on Monday, June 24, as part of the special session Outstanding Scientific Achievement Award Lecture and Banting Medal for Scientific Achievement Award Lecture
Dr. Parker started his lecture with examples of diabetes GWAS studies, which have uncovered independent genetic signals associated with type 2 diabetes predisposition—now numbering over 700—that “underscore the genetic complexity of the disease.”
He likened his work of linking genetic variants to gene expression and chromatin accessibility to his childhood interest of assembling LEGO bricks. In both, seemingly simple parts are assembled in specific ways to form complex structures that do not resemble the components in form or function.
Dr. Parker described how the effects of genetic variants percolate through layers of complexity, starting with the invariant, context-independent layer of the genome and flowing through multiple context-specific layers of epigenomic regulation, the transcriptome, the proteome, and finally specific cell and tissue types, ultimately converging on a complex trait like diabetes predisposition.
Notably, most 90 percent of the type 2 diabetes GWAS signals, i.e., diabetes-associated single-nucleotide polymorphisms, correspond to non-coding regions of the genome, rather than to the protein-coding regions. Dr. Parker said that is indicative of a role for these variants in modulation of gene expression and chromatin structure.
Through seminal work associating diabetes GWAS loci with single-nucleus multi-omics analyses of gene expression and chromatin structure, along with traditional and multiplexed pancreatic tissue imaging analyses, Dr. Parker and colleagues seek to pinpoint the mechanistic links between genetic variants and diabetes susceptibility.
Dr. Parker detailed the steps in the discovery of one locus of interest—RFX6, a transcription factor critical for the development and function of the pancreas—as a beta-cell “hub gene.” Notably, genetic variants enriched in GWAS were associated with disruptions in the transcriptional footprint of RFX6 in islet cells. Mutations in RFX6 have also been associated with neonatal diabetes.
Researchers have recently applied similar single-nucleus multi-omics analyses to skeletal muscle, Dr. Parker noted. These studies have provided insights into the molecular landscape and pathways in specific cell types within skeletal muscle tissue, such as endothelial cells and subsets of muscle fibers, which would not have been possible based on bulk skeletal muscle studies.
Throughout his lecture, Dr. Parker thanked his mentors, mentees, colleagues, and collaborators. He also acknowledged the early-career support he received from the ADA as a 2014 Pathway to Stop Diabetes Award recipient.
“While I’m the one being honored today, the underlying work to achieve this award is the culmination of the efforts of so many,” he said, adding, “Each of these treasured interactions, collaborations, and mentorships have created a patchwork of ideas to come together in this beautiful mosaic. If you look closely enough, you can see the magic happen.”
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