An Enhancer Within Abcb11 Regulates G6pc2 in C57BL/6 Mouse Pancreatic Islets

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• G6PC2, a glucose-6-phosphatase catalytic subunit, is crucial for regulating fasting blood glucose (FBG) by modulating insulin secretion sensitivity in pancreatic β-cells.
• The G6pc2 promoter alone is insufficient for sustained islet-specific expression, indicating the role of distal regulatory elements.

Purpose of the Study:

• To identify and characterize distal enhancers regulating G6pc2 expression.
• To investigate the functional impact of a specific enhancer (enhancer I) on G6pc2 expression and glucose homeostasis.

Main Methods:

• Bioinformatic analysis of human and mouse G6PC2 loci to identify putative enhancers.
• CRISPR-mediated deletion of enhancer I in C57BL/6 mice.
• Analysis of gene expression in isolated islets and assessment of glucose tolerance and FBG in vivo.

Main Results:

• A novel enhancer region (enhancer I) located in the 25th intron of Abcb11 was identified, binding islet-enriched transcription factors.
• CRISPR deletion of enhancer I in mice led to a ~50% reduction in G6pc2 expression in isolated islets.
• Partial G6pc2 reduction enhanced basal insulin secretion but did not affect FBG or glucose tolerance in vivo.

Conclusions:

• Distal enhancers play a significant role in regulating G6pc2 expression in pancreatic islets.
• Targeting enhancer I or similar regulatory elements may offer therapeutic potential for modulating insulin secretion and glucose metabolism.