FBXL19 transcriptionally primes promoters of developmental genes via CDK8-Mediator recruitment [ChIP-seq 1]. Mus musculus

Regulatory elements called CpG islands (CGIs) are associated with the majority of mammalian gene promoters and have been proposed to play an important role in gene expression. The regulatory capacity of CGIs is thought to rely upon a family of proteins that recognise CGIs through their ZF-CxxC DNA binding domains to recruit chromatin-modifying activities to gene promoters. Through studying FBXL19, a poorly characterized ZF-CxxC domain-containing protein, we have discovered that it specifically interacts with the CDK8-Mediator complex in mouse embryonic stem cells (ESCs). Intriguingly, FBXl19 recruits CDK8-Mediator to a subset of CGI-associated promoters of repressed developmental genes in ESCs. We show that FBXL19-dependent recruitment of CDK8 in ESCs is required for the proper induction of the associated genes during ESC differentiation. This is consistent with early embryonic lethality of in FBXl19 deficient mice. Together, our observations highlight a novel role for FBXL19 in priming developmental gene expression, via recruitment of CDK8 to their CGI promoters, in order to support normal gene induction during differentiation and development. Overall design: Binding profile of FBXl19 and its dependency of a functional CxxC domain was determined via performing ChIPseq for epitope-tagged wild type, CxxC point mutant FBXL19 and ΔCxxC FBXL19 in ES cells.