# Functional interaction of transcriptional regulators in endocrine lineage specification

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $674,130

## Abstract

SUMMARY
Reduction in functional insulin-secreting β cells underlies the progression of all forms of diabetes, underscoring
the translational relevance of deciphering molecular pathways regulating the formation, growth, and function of
β cells. The transcriptional networks critical for the proper development, differentiation, and expansion of β cells
work through islet enhancers, super enhancers, and active promoters that form 3D hubs. The homeodomain
transcription factor Pdx1 is a critical member of the β-cell transcriptional network during development and in
postnatal β-cell function. Pdx1 is mutated in monogenic forms of human diabetes and plays critical roles in early
pancreas specification, regulation of organ size, and in β-cell formation, proliferation, and identity. Our
preliminary data reveal that developing β cells exhibit altered subnuclear localization and reduced levels of Pdx1
protein as they advance through the cell cycle. Further, ectopically elevated levels of Pdx1 prevent cell cycle
progression, suggesting that dynamic regulation of expression is required for effective β-cell expansion. We
identify an intrinsically disordered protein region (IDPR) in the Pdx1 C-terminus (aa 207-223). IDPRs, commonly
found within transcription factors, lack fixed secondary structure and are amenable to flexible conformations and
phase separation. IDPRs promote protein-protein interactions and transcriptional hub formation at super
enhancers necessary for coordinated gene regulation. We have found that the Pdx1 C-terminus mediates
interaction with the one cut homeodomain transcription factor Oc1 in multipotent pancreatic progenitor cells to
establish the endocrine gene program, with long-term impact on postnatal islet function and β-cell compensation.
We previously identified the E3 ubiquitin ligase substrate adaptor SPOP as a PDX1 C-terminus partner (via
aa224-238) that mediates ubiquitination and proteasomal degradation of PDX1. Our preliminary data suggest
that SPOP and Oc1 compete for interaction with the Pdx1 C-terminus and that Oc1 protects Pdx1 from SPOP-
mediated degradation. Notably, the C-terminus harbors several diabetes-associated human mutations, one of
which we recently found disrupts the PDX1/SPOP interaction. Thus, we hypothesize that PDX1/OC1
interactions, in part mediated by their IDPRs, regulate Pdx1 stability, cell cycle progression, and pancreatic
endocrine differentiation. This hypothesis will be tested in 3 Aims: (1) To determine the mechanisms whereby
Pdx1 and Oc1 cooperate to establish a chromatin landscape permissive for endocrine differentiation and
proliferation; (2) To define the roles of the Pdx1 and Oc1 IDPRs in protein-protein interaction and pancreas
development; and (3) To define the molecular mechanisms by which the Pdx1 C-terminal domain regulates
protein stability and function during pancreas organogenesis and endocrine differentiation. The impact of human
diabetes-associated mutations will be investigated in th...

## Key facts

- **NIH application ID:** 10755346
- **Project number:** 5R01DK135032-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Maureen A Gannon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $674,130
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755346

## Citation

> US National Institutes of Health, RePORTER application 10755346, Functional interaction of transcriptional regulators in endocrine lineage specification (5R01DK135032-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10755346. Licensed CC0.

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