The human β‐globin locus control region

Abstract

The human b-globin gene locus is the subject of intense study, and over the past two decades a wealth of information has accumulated on how tissue-specific and stage-specific expression of its genes is achieved. The data are extensive and it would be difficult, if not impossible, to formulate a comprehensive model integrating every aspect of what is currently known. In this review, we introduce the fundamental characteristics of globin locus regulation as well as questions on which much of the current research is predicated. We then outline a hypothesis that encompasses more recent results, focusing on the modification of higher-order chromatin structure and recruitment of transcription complexes to the globin locus. The essence of this hypothesis is that the locus control region (LCR) is a genetic entity highly accessible to and capable of recruiting, with great efficiency, chromatinmodifying, coactivator, and transcription complexes. These complexes are used to establish accessible chromatin domains, allowing basal factors to be loaded on to specific globin gene promoters in a developmental stage-specific manner. We conceptually divide this process into four steps: (a) generation of a highly accessible LCR holocomplex; (b) recruitment of transcription and chromatin-modifying complexes to the LCR; (c) establishment of chromatin domains permissive for transcription; (d) transfer of transcription complexes to globin gene promoters.

Epigenetic regulation of normal and malignant hematopoiesis

“…During erythropoiesis, the maturation of erythrocytes is associated with increased expression of a-and b-globin genes, which is required to synthesize large amounts of hemoglobin (B3 Â 10 8 molecules per cell). The b-globin locus is located on chromosome 11 and consists of five genes e, Gg, Ag, d and b which are under the regulation of a locus control region, located 6-22 kb upstream of the e-globin gene (Levings and Bungert, 2002). In non-erythroid cells, these genes exist in a methylated, transcriptionally silent state.…”

Selection of highly specific and sensitive mRNA biomarkers for the identification of blood

“…Blood was chosen for its easy availability, stability and the number of reported markers [6][7][8][9][10][13][14][16][17][19][20]. The following blood markers were included in the study: HBA and HBB are the alpha-and betasubunits of hemoglobin A [21,22]; aminolevulinate synthase 2 (ALAS2) is an erythroid-specific mitochondrial enzyme, that catalyzes the first step in the heme biosynthetic pathway [23]; CD3 gamma molecule (CD3G) is part of the T-cell receptor-CD3 complex, which plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways [24]; ankyrin 1 (ANK1) is an erythrocyte membrane protein, which provides the primary linkage between the membrane skeleton and the plasma membrane [25]; the erythroid form of porphobilinogen deaminase (PBGD) is the third enzyme of the heme biosynthetic pathway [26]; β-spectrin (SPTB) is an erythrocyte membrane protein [27]; Aquaporin (AQP9) is a water channel protein expressed in peripheral leukocytes [28]. AQP9 was chosen as one representative out of nine, all of which were stated by the authors [13] to be co-expressed in vaginal secretion.…”

Isolation of an activator-dependent, promoter-specific chromatin remodeling factor

“…The chromatin structure of the ORF was the same under repressing and activating conditions (2). Removal of promoter nucleosomes is presumed to relieve the repression brought about through their interference with the transcription machinery (5,6) and may be a general feature of eukaryotic genes (7)(8)(9)(10).…”