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Characterisation of chromatin states in erythroid cells from a patient with a unique severe HbH genotype (ATAC-Seq)

ABSTRACT: Analyses of mutations within the a-globin cluster which downregulate a-globin expression and cause a-thalassaemia provide the basis for genetic counselling and pre-natal diagnosis of this common form of anemia. Understanding the mechanisms by which such mutations cause a-thalassemia has established many of the principles by which mammalian genes are regulated and how this goes awry in human genetic disease. ATAC-Seq and NG Capture-C data from an individual (NSE) with a unique a-globin genotype involving a deletion of the main alpha-globin enhancer on one allele and the --/SEA mutation on the other help to address how the human a-globin cluster is normally regulated.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149794 | GEO | 2022/05/06

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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Characterisation of chromatin states in erythroid cells from a patient with a unique severe HbH genotype (ATAC-Seq)

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