LncRNA MALAT1 induces the dysfunction of β cells via reducing the histone acetylation of the PDX-1 promoter in type 1 diabetes

Type 1 diabetes (T1DM) severely threatens human health, and the dysfunction of insulin-secreting β cells in islets is related to the reduced PDX-1 expression. It has been reported that long non-coding RNA MALAT1 regulates β cell function, while the potential mechanism is unclear. Islets were isolated from non-obese diabetic (NOD) mice and wild type (WT) mice. Mouse islets and β cell line (Min6) were stimulated by IL-1β. The expression of MALAT1 was determined using real-time PCR, while the PDX-1 protein expression was determined using western blotting. ChIP-qPCR was carried out to determine the histone acetylation of the PDX-1 promoter. In NOD islets and IL-1β-stimulated Min6 cells, the expression of MALAT1 was increased, while the mRNA and protein levels of PDX-1 were decreased at an age/time-dependent manner. Overexpressing MALAT1 suppressed the H3 histone acetylation of the PDX-1 promoter, inhibiting both mRNA and protein expressions of PDX-1. Knocking down MALAT1 restored the decrease of the histone acetylation of the PDX-1 promoter, as well as the PDX-1 expression, which was reduced by IL-1β stimulation. Under high glucose stimulation, the overexpression of PDX-1 alone restored the insulin secretion which was inhibited by the simultaneous overexpression of MALAT1 and PDX-1. Under high glucose and IL-1β stimulation, the simultaneous knockdown of MALAT1 and PDX-1 reduced the enhancement of the insulin secretion which was raised by knocking down MALAT1 alone. MALAT1 induces the dysfunction of β cells via reducing the H3 histone acetylation of the PDX-1 promoter and subsequently inhibiting the expression of PDX-1, thus suppressing the insulin secretion.