KZFP-mediated variable DNA methylation of a primate-specific transposon is linked to type I diabetes in humans

Abstract

Variable DNA methylation states during early embryonic development overlap with mechanisms of transposon silencing by Kruppel-associated box zinc finger proteins (KZFPs). We investigated the influence of genetic variation in KZFPs and their transposon targets and identified a variably methylated region (VMR) proximal to the human LY6S-AS1 gene linked to an intronic MER11C retrotransposon targeted by the primate-specific KZFP ZNF808. Mendelian randomisation analysis supported a causal link between VMR methylation and type 1 diabetes risk, and H1 stem cells with inactivated ZNF808 showed marked, transient upregulation of the LY6S-AS1 transcript during the early stages of pancreatic development. Loss of function genetic mutations in ZNF808 have previously been linked to pancreatic agenesis and neonatal diabetes in humans, and the VMR was previously associated with levels of insulin secretion in Gambian children. Together this evidence points to a link between KZFP-mediated DNA methylation of LY6S-AS1, and pancreatic development and function at this locus.