Loss of the transcription factor MAFB limits β-cell derivation from human PSCs.

Next generation sequencing studies have highlighted discrepancies in β-cells which exist between mice and men. Numerous reports have identified MAF BZIP Transcription Factor B (MAFB) to be present in human β-cells postnatally, while its expression is restricted to embryonic and neo-natal β-cells in mice. Using CRISPR/Cas9-mediated gene editing, coupled with endocrine cell differentiation strategies, we dissect the contribution of MAFB to β-cell development and function specifically in humans.

Deletion of Gpr27 in vivo reduces insulin mRNA but does not result in diabetes.

Gpr27 is a highly conserved, orphan G protein coupled receptor (GPCR) previously implicated in pancreatic beta cell insulin transcription and glucose-stimulated insulin secretion in vitro. Here, we characterize a whole-body mouse knockout of Gpr27. Gpr27 knockout mice were born at expected Mendelian ratios and exhibited no gross abnormalities.

A Genetic Interaction Map of Insulin Production Identifies Mfi as an Inhibitor of Mitochondrial Fission.

Insulin production by the pancreatic β cell is critical for the glucose homeostasis of the whole organism. Although the transcription factors required for insulin production are known, the upstream pathways that control insulin production are less clear. To further elucidate this regulatory network, we created a genetic interaction map of insulin production by performing ∼20,000 pairwise RNA interference knockdowns of insulin promoter regulators.

In Vivo Deletion of β-Cell Drp1 Impairs Insulin Secretion Without Affecting Islet Oxygen Consumption.

Mitochondria are dynamic organelles that undergo frequent fission and fusion events. Mitochondrial fission is required for ATP production, the tricarboxylic acid cycle, and processes beyond metabolism in a cell-type specific manner. Ex vivo and cell line studies have demonstrated that Drp1, a central regulator of mitochondrial fission, is required for glucose-stimulated insulin secretion (GSIS) in pancreatic β cells.

A Whole-Genome RNA Interference Screen Reveals a Role for in Insulin Transcription and the Unfolded Protein Response.

Insulin production by the pancreatic β-cell is required for normal glucose homeostasis. While key transcription factors that bind to the insulin promoter are known, relatively little is known about the upstream regulators of insulin transcription. Using a whole-genome RNA interference screen, we uncovered 26 novel regulators of insulin transcription that regulate diverse processes including oxidative phosphorylation, vesicle traffic, and the unfolded protein response (UPR).