Abstract
The a- and b-globin gene clusters are subject to several levels of regulation. They are expressed exclusively in the erythroid cells, only during defined periods of development and in a perfectly tuned way, assuring, at any stage of ontogeny, a correct balance in the availability of a- and b-globin chains for hemoglobin assembling. Such a tight control is dependent on regulatory regions of DNA located either in proximity or at great distances from the globin genes in a region characterized by the presence of several DNAse I hypersensitive sites and known as the Locus Control Region. All these sequences exert stimulatory, inhibitory or more complex activities by interacting with transcription factors that bridge these regions of DNA to the RNA polymerase machinery. Many of these factors have now been cloned and the corresponding mouse genes inactivated, shading new light on the metabolic pathways they control. It is increasingly recognized that such factors are organized into hierarchies according to the number of genes and circuits they regulate. Some genes such as GATA-1 and 2 are master regulators that act on large numbers of genes at early stage of differentiation whereas others, like EKLF, stand on the lowest step and control only single or limited number of genes at late stages of differentiation. We will review recent data gathered from expression studies in cell cultures, in transgenic or K.O. murine models as well as from a clinical settings. We will also discuss the development of novel theories on the regulation of the a- and b-globin genes and clusters.
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Abbreviations
- HSC:
-
hematopoietic stem cell
- LCR:
-
locus control region
- HS:
-
(DNase I) hypersensitive site
- Fog:
-
friend of GATA-1
- NF-E:
-
nuclear factor erythroid
- EKLF:
-
erythroid Kruppel-like factor
- FKLF:
-
fetal Kruppel-like factor
- SSE:
-
stage selector element
- SSP:
-
SSE binding protein
- CP2:
-
Caat binding protein 2
- COUP-TFII:
-
chicken ovalbumin upstream promoter–transcription factor II
- XPD:
-
xeroderma pigmentosum D
- ATR-X:
-
α-thalassemia-mental retardation X-linked
- SWI/SNF:
-
switching and/or sucrose nonfermentor
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This work was supported by grants from Assessorato Igiene e Sanità Regione Sardegna: L.R. n. 11 30/4/1990, anno 2000 and by Fondazione Italiana L. Giambrone per la guarigione della Talassemia.
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Cao, A., Moi, P. Regulation of the Globin Genes. Pediatr Res 51, 415–421 (2002). https://doi.org/10.1203/00006450-200204000-00003
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DOI: https://doi.org/10.1203/00006450-200204000-00003
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