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Regulation of alpha-like globin gene expression in murine primitive erythropoiesis (ChIP-seq)

ABSTRACT: Haemoglobin, the oxygen-carrying molecule of red blood cells, at all stages of development comprises a tetramer of two α-like and two β-like globin chains. In humans and mice the highly conserved α- and β-globin loci contain genes encoding globin chains specifically expressed only during the first trimester of gestation (termed embryonic globins) in addition to the genes encoding globin chains expressed throughout adult life. In humans the β-globin locus also encodes a β-like chain that is expressed throughout the second and third trimesters of development; this is termed γ-globin and complexes with α-globin to form fetal haemoglobin (HbF). The sequential activation and repression of the genes at each of these loci throughout development to maturity is termed haemoglobin switching and is a poorly understood process. α-thalassemia, which results from insufficient production of α-globin, is a major global health problem with several hundred thousand sufferers world-wide. The embryonically expressed ζ-globin, encoded by the gene HBZ (Hba-x in mice), can functionally substitute for α-globin in adult erythroid cells. Reactivation of this gene is consequently likely to ameliorate the symptoms of α-thalassemia in individuals with a severe phenotype. Little is currently known about the regulation of ζ-globin expression in terms of both the trans- and cis-acting regulatory elements responsible for high-levels of expression of this gene during embryonic erythropoiesis and its maintenance in a transcriptionally inactive state throughout adult life. Using ATACseq, ChIP-seq and NG Capture C and mutant mouse lines this work aims to identify and define the cis-acting regulatory network underlying zeta-globin expression, and define the contribution of each regulatory element.

ORGANISM(S): Mus musculus

PROVIDER: GSE174593 | GEO | 2021/05/18

REPOSITORIES: GEO

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Project description:Background: The thalassemias are highly diverse at both the molecular and clinical levels. Many of the HBB mutations that result in β-thalassemia are missense mutations in the coding region of the β-globin gene, but a few cause alternative splicing, and interfere with normal processing of the β-globin transcripts. Transcriptome profiling in individuals affected with β-thalassemia, especially in individuals who carry novel mutations in the HBB, may improve our understanding of the heterogeneity and molecular mechanisms of the disease. Methods: Members of a family with a daughter affected with thalassemia intermedia, although her mother was not clinically affected, were examined for physical characteristics, hematological parameters and β-globin gene sequences. We also characterized genome-wide gene expression in the family using RT-qPCR and high-throughput RNA-sequencing mRNA expression profiling of blood. Results: Clinical findings, hematological indices, DNA and RNA sequence analysis of individuals with β-thalassemia, including the description of a novel mutation in the β-globin gene, which introduces a cryptic donor splice site. More than 300 genes are differentially expressed in β-thalassemic blood with many of the DEGs involved in pathways relevant to the clinical management of β-thalassemia. β-thalassemia shows important similarities and differences with sickle cell disease at the transcriptome level. Conclusions: We described the down-regulation of the β-globin gene in β-thalassemia by RNA-sequencing analysis using a sample from an affected individual and her mother, who have a novel mutation in the HBB that creates a cryptic donor splice site. The daughter has a typical β-thalassemia allele as well, and an unexpectedly severe phenotype. The DEGs are enriched in pathways that are directly or indirectly related to β-thalassemia such as hemopoiesis, heme biosynthesis, response to oxidative stress, inflammatory responses, immune responses, control of circadian rhythm, apoptosis, and other cellular activities. We compare our findings with published results of RNA-Sequencing analysis of sickle cell disease (SCD) and erythroblasts from a KLF1-null neonate with hydrops fetalis, and recognize similarities and differences in their transcriptional expression patterns.

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Regulation of alpha-like globin gene expression in murine primitive erythropoiesis (ChIP-seq)

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