Much of our knowledge regarding the actions of islet-enriched transcription factors, key regulators of ? cell differentiation and function, derive from studies in rodents, which is problematic because of differences in islet cell composition, cell architecture, and glucose responsive insulin secretion with humans. Unlike other islet- enriched transcription factors, there is a prominent difference between rodents and humans in the ? cell composition of the MAFA (i.e. (V-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog A) and MAFB regulators. Thus, the dimeric activator in rodents is MafA2 and a heterodimer of MAFA and MAFB in humans. Notably, much evidence suggests that there are distinct functional differences between MafA and MafB, with MafB2 important during development and in the immature ? cell. We will use human EndoC?H2 ? cell lines, human embryonic stem derived ? cells and human islets to elucidate how MAFB2 and MAFA/B control human ? cell activity. Interestingly, a missence variant of human MAFA (S64F) was recently shown to co- segregate with diabetes and insulinomatosis by Drs. Sian Ellard, Andrew Hattersley, and Mrta Korbonits in England. (Insulinomatosis is defined as multicentric insulin-secreting tumors that are not linked with mutations in MEN1 (Multiple Endocrine Neoplasia type 1), which often arises in a familial setting and is associated with diabetes). The phenotype of this variant suggests that MAFA is the newest member of the Maturity-Onset of Diabetes of the Young gene family, an autosomal dominant monogenic form of diabetes often observed in early adulthood. In collaboration with these investigators, we are determining how this mutation impacts MAFA, with our preliminary results supporting gain-of-function properties due to increased protein stability. The identification of this MAFA variant provides evidence for the important role of this transcription factor in human islet ? cell function and diabetes pathogenesis. This idea is also supported by observations of compromised MAFA and MAFB mRNA and protein levels in human type 1 diabetes mellitus (T1D) and T2D ? cells. These data will provide new mechanistic insights into how normal and pathological processes influence transcription factor actions. Our analyses will include the isolation and characterization of the coregulators recruited by MAFB2 and MAFA/B to mediate transcriptional control in human ? cells. The questions being addressed in our experiments will provide knowledge relevant to those developing diagnostic and therapeutic approaches for diabetes.

Public Health Relevance

Human islet ? cells produce the MAFA and MAFB transcription factors, key islet-enriched regulators of rodent cell maturation and adult function. However, only MafA is produced in rodent ? cells postnatally, and, so we will focus on defining mechanistically how the MAFA/B heterodimer influences human ? cell function, expecting this regulator to impart properties uniquely associated with primate cells. In addition, we will define how the S64F MAFA variant effects the activity and proliferation state of human ? cells, a mutation recently identified in patients that can develop both diabetes and multicentric insulin-secreting tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK090570-05A1
Application #
9185163
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2011-07-29
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240
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Conrad, Elizabeth; Dai, Chunhua; Spaeth, Jason et al. (2016) The MAFB transcription factor impacts islet ?-cell function in rodents and represents a unique signature of primate islet ?-cells. Am J Physiol Endocrinol Metab 310:E91-E102

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