The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences

Abstract

Paired box 4 (PAX4) is a key factor in the generation of insulin producing β-cells during embryonic development. In adult islets, PAX4 expression is sequestered to a subset of β-cells that are prone to proliferation and more resistant to stress-induced apoptosis. The importance of this transcription factor for adequate pancreatic islets functionality has been manifested by the association of mutations in PAX4 with the development of diabetes, independently of its etiology. Overexpression of this factor in adult islets stimulates β-cell proliferation and increases their resistance to apoptosis. Additionally, in an experimental model of autoimmune diabetes, a novel immunomodulatory function for this factor has been suggested. Altogether these data pinpoint at PAX4 as an important target for novel regenerative therapies for diabetes treatment, aiming at the preservation of the remaining β-cells in parallel to the stimulation of their proliferation to replenish the β-cell mass lost during the progression of the disease. However, the adequate development of such therapies requires the knowledge of the molecular mechanisms controlling the expression of PAX4 as well as the downstream effectors that could account for PAX4 action.

Molecular Modelling of Islet β-Cell Adaptation to Inflammation in Pregnancy and Gestational Diabetes Mellitus

“…This correlated with decreased expression of β-cell maturity markers such as Ins, MafA or NeuroD and increased expression of the β-cell plasticity gene Pax4, suggesting dedifferentiation of β-cells [108]. Of note, PAX4 per se can also inhibit the expression of Ins and MafA [80], likely further inhibiting β-cell maturation. Using immunoprecipitation assays, we have demonstrated a direct interaction of HMG20A with the promoter region of the Pax4 gene as well as to the first exon of the gene, suggesting a direct regulation of Pax4 expression by HMG20A [108].…”

“…PAX4 is a master regulator of β-cell commitment during development as well as for β-cell plasticity during adulthood [79][80][81]. In mice, the lack of this transcription factor during development causes neonatal death accompanied by severe hyperglycemia.…”

“…Notwithstanding, despite the beneficial effects of PAX4, long term in vivo overexpression of Pax4 in β-cells can cause dedifferentiation of the β-cells leading to the development of hyperglycemia [85]. As such, PAX4 expression/activity must be tightly regulated to permit β-cell expansion without impairing mature function [80]. In this regard, the chromatin factor HMG20A, also known as iBRAF, has become a key element in modulating Pax4 gene expression.…”

Identification of novel variants associated with osteoporosis, type 2 diabetes and potentially pleiotropic loci using pleiotropic cFDR method

“…Variant rs11200594 is located at the region with promotor histone marks (H3K4me3 and H3K9ac) and enhancer histone marks (H3K4me1 and H3K27ac) where changes in it can affect PLEKHA1 gene expression. PAX-4 and HDAC2 bind differentially to the alleles of rs11200594, where PAX-4 is involved in pancreatic islet development as well as differentiation of insulin-producing beta cells and HDAC2 can regulate osteoclastogenesis [62,63]. Moreover, rs11200594 is an eQTL of PLEKHA1 and most of the variants in strong LD (r 2 ≥ 0.8) with rs11200594 within the locus are eQTLs in various tissues including whole blood, adipose, testis and ovary, especially rs71486610 with multiple functions (promotor, DHS (DNase I hypersensitivity sites), eQTL and transcription factor binding site), suggesting that rs11200594 may be a causal variant.…”

Transcriptional regulator PAX4 links Receptor Tyrosine Kinases (RTKs) and cytoskeleton stability in Alzheimer’s disease and type 2 diabetes

“…The transcription factor PAX4 has been shown to be involved in inducing regenerative capacity in insulin-positive islet cells in mice (21,27). PAX4 mutation have also been implicated in T2D (28) and its overexpression leads to β-cell proliferation and reduces apoptosis (29). Only very recently PAX4 has been implicated in denervation in mice (30) and neurodegeneration, especially Parkinson's disease (31).…”