MNX1 prevents somatostatin expression in human beta cells by repressing PERCC1

Area of Science:

• Endocrinology
• Molecular Biology
• Developmental Biology

Background:

• The transcription factor MNX1 (motor neuron and pancreas homeobox 1) is crucial for pancreatic beta cell development and identity in mice.
• Loss of MNX1 in mouse beta cells leads to increased somatostatin (SST) expression through an unknown mechanism.
• Understanding MNX1's role in human beta cells is essential for insights into beta cell plasticity and potential therapeutic strategies.

Purpose of the Study:

• To investigate the role of MNX1 in maintaining human beta cell identity.
• To identify the molecular mechanisms by which MNX1 regulates gene expression in human beta cells.
• To explore the potential implications for therapeutic interventions targeting beta cell function.

Main Methods:

• Utilized the human beta cell line EndoC-BH1 for experiments.
• Employed siRNA to knockdown MNX1 expression and performed bulk RNA sequencing to identify targets.
• Conducted loss-of-function and gain-of-function experiments to elucidate MNX1's regulatory pathways.

Main Results:

• MNX1 knockdown in human beta cells upregulated somatostatin (SST) and its activator HHEX (haematopoietically expressed homeobox).
• PERCC1 (proline and glutamate rich with coiled coil 1) was significantly upregulated upon MNX1 knockdown and acts as an activator of HHEX and SST.
• A regulatory axis involving MNX1, PERCC1, and HHEX was identified, with PERCC1 and HHEX exhibiting positive feedback regulation.

Conclusions:

• Discovered a novel MNX1-PERCC1-HHEX regulatory axis in human beta cells.
• MNX1 maintains beta cell identity by inhibiting PERCC1, a key regulator of SST and HHEX expression.
• This axis offers insights into beta cell plasticity and potential therapeutic targets for preserving beta cell identity.