FUNCTIONAL CHARACTERIZATION OF KRAB ZINC FINGER PROTEINS INVOLVED IN EARLY DEVELOPMENT

Abstract

During early mammalian development, drastic epigenetic reprogramming is required, with any deviation in this process potentially resulting in severe developmental defects. Tripartite motif-containing 28 (Trim28) has been revealed to repress endogenous retroviruses (ERVs) during epigenetic reprogramming. The current Trim28 repression mechanism requires KRAB-Zinc finger proteins (KRAB-ZFPs) to tether TRIM28 to specific ERVs, for the establishment of repressive chromatin marks such as H3K9me3. Despite multiple KRAB-ZFPs having been described to be orchestrated in the TRIM28 regulatory network, their functions and genome-wide coverage remain unknown. We discovered Zfp68 as a novel transcription repressor that targets ERVL-MaLR transposable elements in early embryos, mouse embryonic stem cells (mESCs) and, somatic cells. Through genomic and transcriptomic studies, we identified Zfp68 mediates Trim28 to establish H3K9me3 at bound regions for transcriptional repression. Additionally, we showed removal of the ZFP68/TRIM28 complex results in transcription activation and gene co-option. This phenomenon could form an additional layer of KRAB-ZFP/TRIM28 epigenetic regulation to safeguard epigenome stability.