I will present two studies shedding light on less-explored gene regulatory aspects. Transcriptional enhancers have been extensively studied but their impact on gene silencing kinetics is less well understood. We studied the dynamics of the chromatin and enhancer-RNA landscapes during the silencing of the Kit gene during GATA1-induced erythroid maturation. Surprisingly, we identified transient enhancer-like elements that emerged as Kit transcription diminished. Deletion of one such element accelerated Kit silencing, indicating that its normal role is to delay transcriptional repression. The element, which is initiated by GATA1 is also terminated by GATA1 in a manner dependent on the FOG1-NuRD deacetylase complex. Thus, the transient nature of enhancer elements can be regulated by dynamic co-factor usage. Analysis of data sets from different cell types and species suggests that transiently active enhancer elements at genes undergoing silencing are widespread, and that gene silencing dynamics are finely tuned.
The second study addresses the regulation of upstream antisense transcription (uasTrx) which occurs at the great majority of active gene promoters. Combining acute degradation of the multi-functional transcription factor CTCF with nascent transcription measurements, we found that CTCF specifically suppresses antisense but not sense transcription at hundreds of divergent promoters. Genome editing, chromatin conformation studies and high-resolution transcript mapping revealed that precisely positioned CTCF directly suppresses the initiation of uasTrx, in a manner independent of CTCF’s architectural function. Hence, uasTrx can be under selective transcription factor control.
Transient enhancers, which can be easily missed in heterogenous cell populations or in cells representing a single maturation stage, and elements governing uasTrx expand the regulatory genome in a manner that may aid in the interpretation of eQTLs and disease-associated sequence variants.