?-Thalassemia due to intronic LINE-1 insertion in the ?-globin gene (HBB): molecular mechanisms underlying reduced transcript levels of the ?-globin(L1) allele.

ABSTRACT: We describe the molecular etiology of ?(+)-thalassemia that is caused by the insertion of the full-length transposable element LINE-1 (L1) into the intron-2 of the ?-globin gene (HBB). The transcript level of the affected ?-globin gene was severely reduced. The remaining transcripts consisted of full-length, correctly processed ?-globin mRNA and a minute amount of three aberrantly spliced transcripts with a decreased half-life due to activation of the nonsense-mediated decay pathway. The lower steady-state amount of mRNA produced by the ?-globin(L1) allele also resulted from a reduced rate of transcription and decreased production of full-length ?-globin primary transcripts. The promoter and enhancer sequences of the ?-globin(L1) allele were hypermethylated; however, treatment with a demethylating agent did not restore the impaired transcription. A histone deacetylase inhibitor partially reactivated the ?-globin(L1) transcription despite permanent ?-globin(L1) promoter CpG methylation. This result indicates that the decreased rate of transcription from the ?-globin(L1) allele is associated with an altered chromatin structure. Therefore, the molecular defect caused by intronic L1 insertion in the ?-globin gene represents a novel etiology of ?-thalassemia.

SUBMITTER: Lanikova L 

PROVIDER: S-EPMC4993193 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature