All forms of diabetes are due to a relative deficit of functional beta cells, yet adult human beta cells are resistant to attempts at replication, and serve as a poor experimental model for replicating human beta cells. Because of this paucity of models for adult human beta cell replication, we have developed a large Biorepository of rare human insulinomas, benign pancreatic adenomas that grow and over-secrete insulin, believing that they may provide information that will inform attempts at clues and drug targets and pathways for therapeutic human beta cell regeneration. Recently, we have provided the results of intensive genomic, transcriptomic and bioinformatic analysis of human insulinomas, comparing them to FACS-sorted pure human beta cells. Remarkably, we find that insulinomas display three cardinal features: 1) they almost universally contain recurring mutations, copy number alterations and gene expression abnormalities in members of the Trithorax Group of chromatin modifying enzymes, notably including KDM6A, MLL3 and/or MEN1; 2) they also almost universally display alterations in the Polycomb Repressive Complex of chromatin modifying enzymes and their targets, particularly YY1, EZH2 and H3F3A; 3) they almost universally display abnormalities in the chromosome 11, such as allelic loss of all or part of chromosome 11, and/or allele-specific expression and/or DNA methylation/imprinting abnormalities of the imprinted 11p15 region of chromosome 11, reminiscent of the other beta cell proliferative disorders, such as the Focal Variant of Hyperinsulinism and Beckwith-Wiedemann Syndrome. On the other hand, the mechanisms through with these events lead to beta cell proliferation and while maintaining the beta cell phenotype are unknown. More specifically, exactly how MEN1, KDM6A, MLL3, YY1, EZH2 and H3F3A modulate beta cell function and proliferation are largely unknown. The three Specific Aims of this application address this important knowledge gap.
Aim 1. To Elucidate the Abnormal Pathobiology of Three Key Trithorax Members In Insulinoma vs. Beta Cells.
Aim 2. To Define Abnormal Biology of Three Key Polycomb Repressive Complex Members in Insulinomas vs. Beta Cells.
Aim 3. To Define 3-D Chromosome 11p15 Architecture in Insulinomas and Beta Cells.
240 million people in the world, and more than 30 million in the US, have Type 1 or Type 2 diabetes, both of which result entirely or in part from a lack of human beta cells. We have explored state-of-the-art genomics, transcriptomics and bioinformatics in a large and unique collection of human insulinomas to understand the mechanisms through which they are able to overcome the normal barriers to human beta cell expansion. We have identified six novel categories of genes that regulate human beta cell expansion and function; here, we will explore how these pathways function, elucidating new pathways for human beta cell regenerative drugs.
| Wang, Peng; Karakose, Esra; Liu, Hongtao et al. (2018) Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells. Cell Metab : |
