Cis- and Trans-Acting Expression Quantitative Trait Loci Differentially Regulate Gamma-Globin Gene Expression

Abstract

Genetic association studies have detected two trans-acting quantitative trait loci (QTL) on chromosomes 2, 6 and one cis-acting QTL on chromosome 11 that were associated with fetal hemoglobin (HbF) levels.In these studies, HbF was expressed as a percentage of total hemoglobin or the number of erythrocytes that contain HbF (F-cells). As the g-globin chains of HbF are encoded by two non-allelic genes (HBG2, HBG1) that are expressed at different levels we used normalized gene expression and genotype data fromThe Genotype-Tissue Expression (GTEx)-project to study the effects of cis-and trans-acting HbF expression or eQTL. This allowed us to examine mRNA expression of HBG2 and HBG1individually. In addition to studying eQTL for globin genes we examined genes co-expressed with HBG1, studied upstream regulators of HBG1 co-expressed genes and performed a correlation analysis between HBG2 and HBG1 and known HbF regulators. Our results suggest differential effect of cis and trans-acting QTL on HBG and HBG1 expression. Trans-acting eQTLs have the same magnitude of effect on the expression of both HBG2 and HBG1 while the sole cis-acting eQTL affected only HBG2. Furthermore, the analysis of upstream regulators and the correlation analysis suggested that BCL2L1 might be a new potential transacting HbF activator. HbF is the major modulator of the phenotype of sickle cell anemia and b thalassemia. Depending on the effect size, modification of trans-acting elements might have a greater impact on HbF levels than cis-acting elements alone.

Fetal Hemoglobin in Sickle Hemoglobinopathies: High HbF Genotypes and Phenotypes

“…Disruption of the HBG2 QTL 158 bps upstream of this gene and marked by rs7482144, increased HbF about half as much as disruption of the ZBTB7A and BCL11A binding motifs. Rs7482144 affects only HBG2 , whereas both γ-globin genes are modulated by ZBTB7A and BCL11A, perhaps accounting for this difference [ 30 , 31 ]. The diversity of HbF levels associated with point mutations at the same nucleotide or adjacent nucleotides might be explained by how the physical interactions between the transcription factor and its binding motifs or interactions among the proteins in a transcription factor complex are perturbed.…”