Chromatin Loop Formation in the β-Globin Locus and Its Role in Globin Gene Transcription

Abstract

Although linearly distant along mouse chromosome 7 and human chromosome 11, the mammalian β-globin gene is located in close proximity to the upstream locus control region enhancer when it is actively transcribed in the nuclear chromatin environment of erythroid cells. This organization is thought to generate a chromatin loop between the LCR, a powerful enhancer, and active globin genes by extruding intervening regions containing inactive genes. Loop formation in the β-globin locus requires erythroid specific transcriptional activators, co-factors and insulator-related factors. Chromatin structural features such as histone modifications and DNase I hypersensitive site formation as well as nuclear localization are all involved in loop formation in the locus through diverse mechanisms. Current models envision the formation of the loop as a necessary step in globin gene transcription activation, but this has not been definitively established and many questions remain about what is necessary to achieve globin gene transcription activation.

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

“…23,24 Further characterization of this region, by the use of transgenic animals, indicated that the LCR is absolutely required for high level of expression of the b-globin gene in erythroid cells. [25][26][27][28] The single genetic components of the LCR were identified as hypersensitive sites (HS) to the DNAse I in the chromatin of erythroid cells. 29 The chromatin at the individual HSs is composed of arrays of multiple ubiquitous and lineage-specific transcription factorbinding sites (discussed further below).…”

Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock

“…While other Hox-unrelated gene clusters are regulated coordinately (e.g., see Kim and Dean 2012), this precision in meta-cis regulation associated with temporal collinearity is thus far unique to Hox gene clusters. This time process requires a complete series of genes to be clustered, and hence the physical neighborhood of Hox genes at their genomic loci is a fundamental parameter to ensure a faithful anterior-to-posterior patterning in vertebrates.…”

3.4 Rational Approaches for Transgene Expression: Targeted Integration and Episomal Maintenance

“…The most prominent activity of LCRs is their strong transcription enhancing activity, as was studied in detail in case of the human developmentally regulated β-globin locus [51]. The functional role of LCRs became evident with studies in transgenic mice where it was determined that the LCR was responsible for developmental expression of the ɛ-globin genes [52,53]. LCRs are mostly located upstream of their target gene.…”

“…The most widely accepted model of LCR action is the looping model [53,57]. According to this model the 5' hypersensitive site of the LCR forms a folded structure where the hypersensitive sites are in the core and act as docking site for the transcription factors.…”