Epigenetic Control of Cell Fate Decisions by Enhancer-Derived Long Noncoding RNAs

The development of mammals from conception to adult involves trillions of cell fate decisions that must be made with 4-dimensional precision to form the myriad of architecturally sculpted and intricately connected bones, muscles and organs. The spatiotemporal control of this developmental symphony resides in genetic loci termed enhancers, of which ~1 million exist in the human genome. Enhancers have long been thought to act as sites for the binding of transcription factors that are brought into contact with target gene promoters by chromatin looping. However, enhancers are, in fact, genes that produce alternatively spliced and often modified long noncoding RNAs. Enhancer-derived RNAs act as scaffolds to recruit chromatin modifying proteins and transcription factors containing intrinsically disordered regions (which are subject to a multitude of posttranslational modifications) into phase separated domains for the feed forward control of developmental ontogeny.