ZFP92, a KRAB domain zinc finger protein enriched in pancreatic islets, binds to B1/Alu SINE transposable elements and regulates retroelements and genes

Repressive KRAB domain-containing zinc-finger proteins (KRAB-ZFPs) are abundant in mammalian genomes and contribute both to the silencing of transposable elements (TEs) and to the regulation of developmental stage- and cell type-specific gene expression. Here we describe studies of zinc finger protein 92 (Zfp92), an X-linked KRAB-ZFP that is highly expressed in pancreatic islets of adult mice, by analyzing global Zfp92 knockout (KO) mice. Physiological, transcriptomic and genome-wide chromatin binding studies indicate that the principal function of ZFP92 in mice is to bind to and suppress the activity of B1/Alu type of SINE elements and modulate the activity of surrounding genomic entities. Deletion of Zfp92 leads to changes in expression of select LINE and LTR retroelements and genes located in the vicinity of ZFP92-bound chromatin. The absence of Zfp92 leads to altered expression of specific genes in islets, adipose and muscle that result in modest sex-specific alterations in blood glucose homeostasis, body mass and fat accumulation. In islets, Zfp92 influences blood glucose concentration in postnatal mice via transcriptional effects on Mafb, whereas in adipose and muscle, it regulates Acacb, a rate-limiting enzyme in fatty acid metabolism. In the absence of Zfp92, a novel TE-Capn11 fusion transcript is overexpressed in islets and several other tissues due to de-repression of an IAPez TE adjacent to ZFP92-bound SINE elements in intron 3 of the Capn11 gene. Together, these studies show that ZFP92 functions both to repress specific TEs and to regulate the transcription of specific genes in discrete tissues. Author summaryNearly half of the genomic DNA in mammals is comprised of transposable genetic elements (TEs) that provide a massive source of sequence diversity and regulatory activity. Most TEs are silenced by host factors that include KRAB domain-containing zinc-finger proteins (ZFPs), the majority of which remain uncharacterized. In this study, we analyzed mice that lack Zfp92, a mammalian conserved KRAB-ZFP that is highly expressed in pancreatic islets. We found that Zfp92 principally binds to short interspersed nuclear elements (SINEs) and modulates the activity of these and other TEs and nearby genes. Zfp92 positively regulates the expression of Mafb, a transcription factor important for normal islet development and function, and Acacb, an enzyme important for lipolysis in adipose and muscle tissues. The absence of Zfp92 causes the re-activation of an IAPez TE in intron 3 of the Capn11 gene, resulting in the marked overexpression of a novel TE-Capn11 fusion transcript in islets and several other tissues. These findings provide another example of how TEs and their partnering KRAB-ZFPs may affect the regulation and function of nearby genes, thereby contributing in important ways to cellular development and function.