Human fetal globin gene expression is regulated by LYAR

Ju, Junyi; Wang, Ying; Liu, Ronghua; Zhang, Yichong; Xu, Zhen; Wang, Yadong; Wu, Yupeng; Liu, Ming; Cerruti, Loretta; Zou, Fengwei; Ma, Chi; Fang, Ming; Tan, Renxiang; Jane, Stephen M.; Zhao, Quan

doi:10.1093/nar/gku718

Cited by 36 publications

(45 citation statements)

References 53 publications

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“…Furthermore, seven linkage disequilibrium (LD) blocks containing 163 out of 271 common SNPs were identified in the 80-kb region ( Figure S1) 6 The analysis showed that SNPs rs368698783 was identified as a critical variant of ameliorating factors (HR ¼ 0.552, p ¼ 3.029 3 10 À14 ) after wellknown mutations at KLF1 and HBB in a ranking of Hazard ratio (Table 1). These results together with rs368698783 embedded within a highly conserved hexanucleotide LYAR-binding motif required for methylation-related g-globin gene silencing as previously described, 22 suggested that rs368698783-mediated epigenetic regulation of HbF elevation might be involved in the amelioration of b-thalassemia severity.…”

Section: ]-Hbg2 [Mim 142250]-hbg1 [Mim 142200]-hbd [Mim 142000]supporting

confidence: 77%

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A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression

Chen

Zuo

Zhang

et al. 2017

The American Journal of Human Genetics

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A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of b-thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis-variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the b-globin cluster using capture-based next-generation sequencing of 1142 Chinese b-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single-nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) blocks. A Ly1 antibody reactive (LYAR)-binding motif disruptive rSNP rs368698783 (G/A) from LD block 5 in the proximal promoter of hemoglobin subunit gamma 1 (HBG1) was found to be a significant predictor for b-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. We found this rSNP accounted for 41.6% of b-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. We uncovered that the minor allele of the rSNP triggers the attenuation of LYAR and two repressive epigenetic regulators DNA methyltransferase 3 alpha (DNMT3A) and protein arginine methyltransferase 5 (PRMT5) from the HBG promoters, mediating allele-biased g-globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from b-thalassemia persons. The present study demonstrates that this common rSNP in the proximal A g-promoter is a major genetic modifier capable of ameliorating the severity of thalassemia major through the epigenetic-mediated regulation of the delayed fetal-to-adult Hb switch and provides potential targets for the treatment of b-hemoglobinopathy.

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Section: ]-Hbg2 [Mim 142250]-hbg1 [Mim 142200]-hbd [Mim 142000]supporting

confidence: 77%

“…22 However, the underlying mechanisms driving epigenetic regulation of Hb switching involved in ameliorating b-thalassemia severity are largely unclear.…”

Section: ]-Hbg2 [Mim 142250]-hbg1 [Mim 142200]-hbd [Mim 142000]mentioning

confidence: 99%

A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression

Chen

Zuo

Zhang

et al. 2017

The American Journal of Human Genetics

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“…Because there is no significant difference in the expression of these TALEs, it is presumed that TALE2a does not appear to have enough binding affinity to its target. TALE5 is designed to target the LYAR 40 site that is about 20 bp downstream of fetal-globin gene transcription start site, as mutation of LYAR often results in HPFH. 41 However, TALE5 may not have enough binding affinity even if it binds the LYAR site to displace the transcriptional machinery, and therefore downstream targeting will not be beneficial.…”

Section: Discussionmentioning

confidence: 99%

High level of fetal-globin reactivation by designed transcriptional activator-like effector

et al. 2020

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Key Points• TALEs targeted to the g-globin gene promoters reactivated their mRNA expression more than 70-fold with a collateral reduction in b-globin mRNA.• At day 19 of CD34 erythroid differentiation, TALEs increased g-globin more than 40fold in mRNA level and up to 70% of the total globin protein.The fetal-to-adult hemoglobin switch has been a focus of a long-standing effort to potentially treat sickle cell disease and b thalassemia by induction of fetal hemoglobin. In a continuation of this effort, we designed specific transcriptional activator-like effectors (TALEs) to target both the G g and A g-globin promoters. We fused the TALEs to a LIM domain binding protein (Ldb1) dimerization domain, followed by a T2A green fluorescent protein (GFP) cassette, which were assembled into a lentiviral vector. To prevent deletions caused by the repeats of TALEs during the lentivirus packing process, we changed the TALE encoding DNA by codon optimization. Intriguingly, 5 of 14 TALEs showed forced reactivation of fetalglobin expression in human umbilical cord blood-derived erythroid progenitor (HUDEP-2) cells, with a significant increase in the g-globin mRNA level by more than 70-fold. We also observed a more than 50% reduction of b-globin mRNA. High-performance liquid chromatography analysis revealed more than 30% fetal globin in TALE-induced cells compared with the control of 2%. Among several promoters studied, the b-globin gene promoter with the locus control region (LCR) enhancer showed the highest TALE expression during CD34 erythroid differentiation. At day 19 of differentiation, 2 TALEs increased fetalglobin expression more than 40-fold in the mRNA level and up to 70% of the total globin protein. These TALEs have potential for clinical translation.

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“…In an attempt to identify Myc target genes potentially important for the survival of Myc over-expressing cancer cells, we have identified a canonical E-Box at the gene core promoter of LYAR, and confirmed that N-Myc up-regulates LYAR expression by binding to its gene core promoter 4 . As a nucleolar and nuclear protein with zinc finger DNA-binding motifs, LYAR is known to suppress gene transcription by forming a protein complex with the protein arginine methyltransferase PRMT5 at target gene promoters 5 . We have confirmed through Affymetrix microarray gene expression study, gene set enrichment analysis and chromatin immunoprecipitation assay that LYAR considerably suppresses the transcription of oxidative stress genes, including SLC7A11, ULBP1, HMOX1 and CHAC1 4 .…”

supporting

confidence: 57%