SIX2 and SIX3 coordinately regulate functional maturity and fate of human pancreatic β cells

Abstract

The physiological functions of many vital tissues and organs continue to mature after birth, but the genetic mechanisms governing this postnatal maturation remain an unsolved mystery. Human pancreatic β-cells produce and secrete insulin in response to physiological cues like glucose, and these hallmark functions improve in the years after birth. This coincides with expression of the transcription factors SIX2 and SIX3, whose functions in native human β-cells remain unknown. Here, we show that shRNA-mediated SIX2 or SIX3 suppression in human pancreatic adult islets impairs insulin secretion. However, transcriptome studies revealed that SIX2 and SIX3 regulate distinct targets. Loss of SIX2 markedly impaired expression of genes governing β-cell insulin processing and output, glucose sensing, and electrophysiology, while SIX3 loss led to inappropriate expression of genes normally expressed in fetal β-cells, adult a-cells and other non-β-cells. Chromatin accessibility studies identified genes directly regulated by SIX2. Moreover, β-cells from diabetic humans with impaired insulin secretion also had reduced SIX2 transcript levels. Revealing how SIX2 and SIX3 govern functional maturation and maintain developmental fate in native human β-cells should advance β-cell replacement and other therapeutic strategies for diabetes.

Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells

“…6e-f and Supplementary Table 7). Transcription factors involved in beta cell differentiation (SIX2, HOPX, ZBTB20) 51,55,56 Glycolysis and TCA cycle Disallowed genes and cell cycle inhibition (CEBP transcription factor family 57 , and SCRT1 58,59 ), were also upregulated in S7w6 SC-beta cells, together with ligands (WNT4, TFF3) 4,60 and receptors associated with beta cell function (GCGR, GABRA2, FFAR1) 61 (Fig. 6f).…”

Relationships between type 2 diabetes, cell dysfunction, and redox signaling: A meta‐analysis of single‐cell gene expression of human pancreatic α‐ and β‐cells

“…SIX3 has been identified as a transcription factor that governs functional β-cell maturation and may be a potential target for β-cell dysfunction in T2DM. 47 As outlined in Figure 6, lipotoxicity and glucotoxicity associated with T2DM increase oxidative stress and can increase NFE2L2 activation. As expected, αand β-cells from T2DM donors have increased NFE2L2 activation.…”

Discovering signaling mechanisms governing metabolism and metabolic diseases with Drosophila

“…In fly IPCs, RNAi-mediated suppression of CG9650 (BCL11A) or fascetto (PRC1) led to increased circulating levels of insulin; remarkably, loss of BCL11A in primary human b cells or mouse b cells also led to increased insulin output (Park et al, 2014;Peiris et al, 2018), while induction of CG9650 in IPCs or BCL11A in b cells led to reduced insulin output. Targeted suppression of optix in IPCs led to reduced insulin secretion, and recent studies show that SIX2 loss in human b cells also leads to reduced glucose-dependent insulin output (Bevacqua et al, 2021). In these examples, fly studies correctly predicted the direction of islet b cell phenotypes arising from genetic loss of function.…”

“…Changes of insulin production and output were distinct or not detected after shRNA-mediated gene suppression in the fly fat body, demonstrating specific requirements for these factors in fly IPCs (Park et al, 2014;Peiris et al, 2018) Discovering regulators of pancreatic islet function with flies Genetic and physiological homologies between fly IPCs and islet b cells predicted that discovery of IPC regulators could unveil conserved mechanisms governing insulin secretion. Multiple recent studies have supported this heuristic (Bevacqua et al, 2021;Peiris et al, 2018). Peiris et al (2018) investigated the in vivo function of fly genes orthologous to imputed human diabetes risk genes without known roles in b cells (Mahajan et al, 2018).…”