Phase Separation and Transcription Regulation: Are Super-Enhancers and Locus Control Regions Primary Sites of Transcription Complex Assembly?

It is proposed that the multiple enhancer elements associated with locus control regions and super-enhancers recruit RNA polymerase II and efficiently assemble elongation competent transcription complexes that are transferred to target genes by transcription termination and transient looping mechanisms. It is well established that transcription complexes are recruited not only to promoters but also to enhancers, where they generate enhancer RNAs. Transcription at enhancers is unstable and frequently aborted. Furthermore, the Integrator and WD-domain containing protein 82 mediate transcription termination at enhancers. Abortion and termination of transcription at the multiple enhancers of locus control regions and super-enhancers provide a large pool of elongation competent transcription complexes. These are efficiently captured by strong basal promoter elements at target genes during transient looping interactions.

Engineering Globin Gene Expression.

Hemoglobinopathies, including sickle cell disease and thalassemia, are among the most common inherited genetic diseases worldwide. Due to the relative ease of isolating and genetically modifying hematopoietic stem and progenitor cells, recent gene editing and gene therapy strategies have progressed to clinical trials with promising outcomes; however, challenges remain and necessitate the continued exploration of new gene engineering and cell transplantation protocols. Current gene engineering strategies aim at reactivating the expression of the fetal γ-globin genes in adult erythroid cells. The γ-globin proteins exhibit anti-sickling properties and can functionally replace adult ß-globin. Here, we describe and compare the current genetic engineering procedures that may develop into safe and efficient therapies for hemoglobinopathies in the near future.