Vainorius, G. | Search bioRxiv

bioRxiv2021

Stem cell specific interferon stimulated gene expression is regulated by the formative pluripotency network through IRF1

Stem cells intrinsically express a subset of genes which are normally associated with interferon stimulation, and thus the innate immunity response. Expression of these interferon stimulated genes (ISG) in stem cells is independent of external stimuli such as viral infection. Here we show that the interferon regulatory factor 1, Irf1, is directly controlled by the murine formative pluripotency gene regulatory network and therefore upregulated in the transition from naive to formative pluripotency. IRF1 in turn binds to regulatory regions of a conserved set of ISGs and is required for their faithful expression in formative pluripotent cells. IRF1 also binds to an enhancer of the formative pluripotency transcription factor Oct6 and is partially required for upregulation of Oct6. IRF1 therefore acts as a link between the formative pluripotency network and the regulation of innate immunity genes in formative pluripotency.

developmental biology↗

bioRxiv2021

ZFP462 targets heterochromatin to transposon-derived enhancers restricting transcription factor binding and expression of lineage-specifying genes

ZNF462 haploinsufficiency is linked to Weiss-Kruszka Syndrome, a genetic disorder characterized by a range of neurodevelopmental defects including Autism. Though it is highly conserved in vertebrates and essential for embryonic development the molecular functions of ZNF462 are unclear. We identified its murine homolog ZFP462 in a screen for epigenetic gene silencing in mouse embryonic stem cells (mESCs). Here, we show ZFP462 safeguards neural lineage specification by targeting the H3K9-specific histone methyltransferase complex G9A/GLP to mediate epigenetic silencing of endodermal genes. ZFP462 binds to thousands of transposable elements (TEs) that harbor ESC- and endoderm-specific transcription factor (TF) binding sites and act as enhancers. Through physical interaction with G9A/GLP, ZFP462 seeds heterochromatin at TE-derived enhancers restricting the binding of core pluripotency TFs OCT4 and SOX2. Loss of ZFP462 in ESCs results in increased chromatin accessibility at target sites and ectopic expression of endodermal genes. Taken together, ZFP462 restricts TF binding and subsequent endodermspecific gene activation by conferring lineage and locus-specificity to the broadly expressed epigenetic regulator G9A/GLP. Our results suggest that aberrant activation of endodermal genes in the neuronal lineage underlies ZNF462-associated neurodevelopmental pathology.

genetics↗