Transposable Elements and Their KRAB-ZFP Controllers Regulate Gene Expression in Adult Tissues

KRAB-containing zinc finger proteins (KRAB-ZFPs) are early embryonic controllers of transposable elements (TEs), which they repress with their cofactor KAP1 through histone and DNA methylation, a process thought to result in irreversible silencing. Using a target-centered functional screen, we matched murine TEs with their cognate KRAB-ZFP. We found the paralogs ZFP932 and Gm15446 to bind overlapping but distinguishable subsets of ERVK (endogenous retrovirus K), repress these elements in embryonic stem cells, and regulate secondarily the expression of neighboring genes. Most importantly, we uncovered that these KRAB-ZFPs and KAP1 control TEs in adult tissues, in cell culture and in vivo, where they partner up to modulate cellular genes. Therefore, TEs and KRAB-ZFPs establish transcriptional networks that likely regulate not only development but also many physiological events. Given the high degree of species specificity of TEs and KRAB-ZFPs, these results have important implications for understanding the biology of higher vertebrates, including humans. [Display omitted] •Large-scale functional screen matches KRAB-ZFPs to transposable element (TE) targets•ZFP932 and its paralog Gm15446 regulate different endogenous retrovirus K subsets•KRAB-ZFPs/KAP1 regulate TEs in somatic cells via histone modifications•KRAB-ZFPs/KAP1 use TE-based platforms to regulate adult tissue cellular gene expression KRAB-ZFPs and KAP1 are embryonic controllers of transposable elements (TEs) thought to irreversibly silence TEs and thus be dispensable in the adult. Ecco et al. demonstrate that these modulators continue to control TE expression in adult tissues, where they also act to control expression of neighboring cellular genes.