Variants of ZBTB7A (LRF) and its β-globin gene cluster binding motifs in sickle cell anemia.
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ABSTRACT:
SUBMITTER: Shaikho EM
PROVIDER: S-EPMC6733020 | biostudies-literature | 2016 Jul
REPOSITORIES: biostudies-literature
Publications
Variants of ZBTB7A (LRF) and its β-globin gene cluster binding motifs in sickle cell anemia.
Shaikho Elmutaz M EM Habara Alawi H AH Alsultan Abdulrahman A Al-Rubaish A M AM Al-Muhanna Fahad F Naserullah Z Z Alsuliman A A Qutub Hatem O HO Patra P K PK Sebastiani Paola P Baltrusaitis Kristin K Farrell John J JJ Jiang Zhihua Z Luo Hong-Yuan HY Chui David H K DH Al-Ali Amein K AK Steinberg Martin H MH
Blood cells, molecules & diseases 20160413
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Project description:Genes encoding the human β-like hemoglobin proteins undergo a developmental switch from fetal γ-globin to adult β-globin expression at around the time of birth. β-hemoglobinopathies, such as sickle cell disease and β-thalassemia, result from mutations affecting the adult β-globin gene. The only treatment options currently available carry significant side-effects. Analyses of heritable variations in fetal hemoglobin (HbF) levels have provided evidence that reactivation of the silenced fetal γ-globin genes in adult erythroid cells is a promising therapy. The γ-globin repressor BCL11A has become the major focus with several studies investigating its regulation and function as a first step to inhibiting its expression or activity. However, a second repression mechanism has recently been shown to be mediated by the transcription factor ZBTB7A/LRF, suggesting that understanding the regulation of ZBTB7A may also be useful. Here we show that KLF1 directly drives expression of ZBTB7A in erythroid cells by binding to its proximal promoter. We have also uncovered an erythroid-specific regulation mechanism, leading to the upregulation of a novel ZBTB7A transcript in the erythroid compartment. The demonstration that ZBTB7A, like BCL11A, is a KLF1 target gene also fits with the observation that reduced KLF1 expression or activity is associated with HbF derepression.
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