A permissive chromatin state regulated by ZFP281-AFF3 in controlling the imprinted Meg3 polycistron. Mus musculus

Genomic imprinting is an epigenetic regulation which leads to gene expression in a parent-of-origin specific manner. Previously we have demonstrated that AFF3, the central component of Super Elongation Complex-like 3 (SEC-L3), can specifically bind both the intergenic differentially methylated region (IG-DMR) and the enhancer within the imprinted Dlk1-Dio3 locus to regulate the expression of the Meg3 polycistron. However, the mechanism underlying how AFF3 can interact with distinct chromatin regulatory elements remains unknown. Here, we demonstrate that AFF3 is associated with the Krüppel-like zinc finger protein ZFP281. ZFP281 is required for the recruitment of AFF3 to the enhancer and regulates the allele-specific expression of the Meg3 polycistron in mouse embryonic stem (ES) cells at the transcriptional elongation level. Our genome-wide analyses further identify ZFP281 as a critical factor generally associating with AFF3 at enhancers and functioning together with AFF3 in regulating the expression of a subset of gene. Our study suggests that different zinc finger proteins can function as molecular switchers to regulate the context-dependent function of AFF3 and set a balanced chromatin state for maintaining the allele specific expression pattern of the imprinted Dlk1-Dio3 locus. PLEASE BE AWARE THAT THE SUBMITTER REQUESTED DELETION OF BIGWIG AND PEAK-CALL FILES POST-PUBLICATION. PLEASE CONTACT SUBMITTER FOR FURTHER INFORMATION. Overall design: ChIP-seq of ZFP281 in mES cells. ChIP-seq of Pol II and AFF3 in mES cells after ZFP281 shRNA and non-targeting shRNA. ChIP-seq of ZFP281 in ZFP57 WT and KO ES cells. RNA-seq of mES cells after ZFP281 shRNA and non-targeting shRNA.