Identification of direct transcriptional targets of NFATC2 that promote β cell proliferation

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• The transcription factor NFATC2 (Nuclear Factor of Activated T-cells 2) is known to induce beta cell proliferation.
• Genomic targets mediating NFATC2's role in beta cell proliferation remain largely unidentified.

Purpose of the Study:

• To identify NFATC2's genomic targets and understand their role in beta cell proliferation.
• To investigate the involvement of the FOXP family and Nr4a1 in NFATC2-mediated beta cell proliferation.

Main Methods:

• Integration of gene expression data with NFATC2 genomic binding sites in human islets.
• Analysis of endocrine-specific Foxp1, Foxp2, and Foxp4 triple-knockout mouse models.
• Deletion studies of Nr4a1 to assess its role in NFATC2-induced proliferation.
• Integration of noncoding RNA expression, chromatin accessibility, and NFATC2 binding sites.

Main Results:

• Approximately 2200 NFATC2 transcriptional targets were identified, enriched for cell cycle regulators.
• FOXP family transcription factors cooperate with NFATC2 to regulate beta cell proliferation.
• NFATC2 induced beta cell proliferation in both mouse and human islets, while NFATC1 showed this effect only in human islets.
• Approximately 250 direct NFAT targets in human islets were identified, including Nr4a1.
• Deletion of Nr4a1 significantly reduced NFATC2-induced beta cell proliferation.
• NFATC2-dependent enhancer loci mediating beta cell proliferation were identified.

Conclusions:

• NFATC2 drives beta cell proliferation through regulation of cell cycle genes and direct induction of Nr4a1.
• The FOXP family of transcription factors plays a collaborative role with NFATC2 in regulating beta cell proliferation.
• NFATC2-dependent enhancers are critical regulatory elements for beta cell proliferation.