Transcription regulation by distal enhancers

Abstract

G enome-wide chromatin profiling efforts have shown that enhancers are often located at large distances from gene promoters within the non-coding genome. Whereas enhancers can stimulate transcription initiation by communicating with promoters via chromatin looping mechanisms, we propose that enhancers may also stimulate transcription elongation by physical interactions with intronic elements. We review here recent findings derived from the study of the hematopoietic system. IntroductionThe development of multicellular organisms relies upon the capacity of stem and progenitor cells to respond to their microenvironment and differentiate upon exposure to specific stimuli. This multi-step process involves complex epigenetic changes within regulatory transcriptional networks, which contribute to the timely activation and repression of key developmental genes. Transcription of mammalian genes relies on the presence of a variety of cis-DNA regulatory sequences such as promoters and enhancers. Whereas gene promoters can be relatively easy to identify (i.e., at the 5' end of transcriptional units), locating and characterizing enhancers is far more complicated. Transgenic experiments carried out over the last few decades have taught us important lessons about transcriptional enhancers and genomic organization. Attempts to express transgenes in animals, under the control of endogenous promoter sequences, often resulted in weak

Chromatin looping as a target for altering erythroid gene expression

“…The spacing between enhancers and target genes can be very large when measured in the linear genome . However, studies examining individual gene loci and the whole genome using chromosome conformation capture (3C) and related technologies show that active enhancers exist in physical proximity to their target genes in the nuclear space, a phenomenon referred to as chromatin looping . Other studies reveal that enhancers are sites of RNA polymerase II (Pol II) recruitment and noncoding transcription .…”

MYC and Chromatin

“…The unlikely prospect that such expanses are spanned by linear alterations in DNA structure, or assembly of vast protein bridges, led early to the notion that enhancers must function by looping out intervening DNA and engaging in short-range protein-protein contacts with promoter-bound factors. And for the most part this notion appears correct [91,92]. As with all things connected to MYC, control of its transcription by the action of enhancers is a complex topic, with no unifying model to explain the regulation or deregulation of MYC in all relevant contexts [93].…”

EKLF/KLF1, a Tissue-Restricted Integrator of Transcriptional Control, Chromatin Remodeling, and Lineage Determination

“…Together with the effects at the globin locus, these data suggest that the presence of KLF1 is critical for transcription initiation in facilitating the formation of an open chromatin configuration at target loci. These data raise the possibility that in addition to transcription initiation, KLF1 also plays a role in regulating transcription elongation in erythroid cells (67), since the interaction between the upstream LCR and the proximal ␤-globin promoter, whose 3D chromatin structure requires KLF1 (56,58), aids in establishing a postinitiation transcription elongation complex (68,69). KLF1 is also recruited to the ␣-globin promoter and one of its upstream enhancer elements at late stages of differentiation (60,70), possibly aiding in intrachromosomal interactions, preinitiation complex recruitment, and the transition from a poised to an elongating transcriptional state (70).…”