Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of beta cell function. Here, we show that an lncRNA-transcribed antisense to Pax6, annotated as Pax6os1/PAX6-AS1, was upregulated by high glucose concentrations in human as well as murine beta cell lines and islets. Elevated expression was also observed in islets from mice on a high-fat diet and patients with type 2 diabetes. Silencing Pax6os1/PAX6-AS1 in MIN6 or EndoC-βH1 cells increased several beta cell signature genes’ expression. Pax6os1/PAX6-AS1 was shown to bind to EIF3D, indicating a role in translation of specific mRNAs, as well as histones H3 and H4, suggesting a role in histone modifications. Important interspecies differences were found, with a stronger phenotype in humans. Only female Pax6os1 null mice fed a high-fat diet showed slightly enhanced glucose clearance. In contrast, silencing PAX6-AS1 in human islets enhanced glucose-stimulated insulin secretion and increased calcium dynamics, whereas overexpression of the lncRNA resulted in the opposite phenotype.
function. Here, we show that an lncRNA transcribed antisense to Pax6 annotated as
Pax6os1/PAX6-AS1 was upregulated by high glucose concentrations in human as well
as murine beta-cell lines and islets. Elevated expression was also observed in islets
from mice on a high-fat-diet and patients with type 2 diabetes. Silencing
Pax6os1/PAX6-AS1 in MIN6 or EndoC-βH1-cells increased several β-cell signature
genes` expression. The lncRNA was shown to bind to EIF3D, indicating a role in
translation of specific mRNAs, as well as to histones H3 and H4, suggesting a role in
histone modifications. Important interspecies differences were also found, with a
stronger phenotype in humans. Only female Pax6os1 null mice fed a high-fat-diet
showed slightly enhanced glucose clearance. In contrast, silencing PAX6-AS1 in
human islets enhanced glucose-stimulated insulin secretion and increased calcium
dynamics, while overexpression of the lncRNA resulted in the opposite phenotype.