A satellite DNA array barcodes chromosome 7 and regulates totipotency via ZFP819

Mammalian genomes are a battleground for genetic conflict between repetitive elements (REs) and KRAB-zinc finger proteins (KZFPs). We explored whether KZFPs can regulate cell fate by employing Zfp819, which targets a satellite DNA array, ZP3AR. ZP3AR coats a megabase region of chromosome 7 that encompasses genes encoding ZSCAN4, a master transcription factor of totipotency. Depleting Zfp819 in mouse embryonic stem cells (mESCs) causes them to transition to a 2-cell (2C)-like state, whereby the ZP3AR array switches from a poised to an active enhancer state. This is accompanied by a global eviction of heterochromatin roadblocks, which we link to decreased SETDB1 stability. These events result in transcription of active LINE-1 elements and a block in differentiation. In sum, ZFP819 and TRIM28 partner up to close chromatin across Zscan4, allowing exit from totipotency. We propose that satellite DNAs may control developmental fate transitions through the barcoding and switching off of master transcription factor genes. Identification of how ZFP819 and its co-opted satellite repeat, ZP3AR, influence cell fate transitions through chromatin and gene expression changes.