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414 IGF2BP1 Orchestrates Post-Transcriptional Control of Globin Switching through Direct Binding to Globins and Their Regulators

Program: Oral and Poster Abstracts
Type: Oral
Session: 112. Thalassemia and Globin Gene Regulation: We're Going to Catch a Big One: Towards Targeted Therapies in Thalassemia
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Hemoglobinopathies, Diseases
Sunday, December 8, 2024: 10:45 AM

Steven Coyne, PhD1*, Ting Wu, PhD1*, Divya Vinjamur, PhD2*, Mir Hossain, PhD1* and Daniel E. Bauer, MD, PhD3,4

1Dept. of Hematology/Oncology, Boston Children's Hospital, Boston, MA
2Boston Children's Hospital, Boston, MA
3Department of Pediatrics, Harvard Medical School, Boston, MA
4Hematology/Oncology, Boston Children's Hospital, Boston, MA

Despite over a century of work on hemoglobinopathies, a comprehensive understanding of hemoglobin switching and factors regulating hemoglobin expression remains incomplete even as the first CRISPR/Cas9 gene therapy has obtained approvals for the treatment of transfusion-dependent β-thalassemia and sickle cell disease.

We studied factors related to the heterochronically silenced m6A RNA-binding protein IGF2BP1 which has been identified as a positive regulator of fetal hemoglobin expression by directly suppressing BCL11A expression. In contrast to this observation, post-transcriptional control by IGF2BP1 generally acts through improving the translation and mRNA stability of IGF2BP1 target mRNAs in an m6A-dependent manner. To better characterize the IGF2BP1-mediated mechanism responsible for control of fetal hemoglobin expression, we assessed whether BCL11A was required for IGF2BP1-mediated regulation of fetal hemoglobin and discovered a direct BCL11A-independent mechanism. Additionally, we characterize a heretofore poorly understood BCL11A-dependent mechanism for IGF2BP1 in regulating fetal hemoglobin expression.

We developed a luminescent transgenic reporter to disentangle BCL11A­­-dependent and newly identified BCL11A-independent mechanisms and used this system to discover that IGF2BP1 directly supports the translation of HBG mRNA in a manner requiring intact stop codon-proximal m6A motifs which are absent from the HBB mRNA.

Hemoglobin switching relies on a set of heterochronically regulated transcription factors, miRNAs, and RNA-binding proteins. This work identifies a novel mode of direct post-transcriptional regulation of HBG mRNA by a heterochronically regulated RNA-binding protein, IGF2BP1, that was previously described to regulate HBG indirectly via BCL11A. This work shows that HBG mRNA is bound directly by IGF2BP1 which supports HBG translation. HBB, not normally directly regulated by IGF2BP1, becomes responsive to IGF2BP1 overexpression upon addition of the HBG-derived stop codon-proximal m6A sites to an HBB transgene, a strategy with potential to be exploited for the improved expression of globin transgenes for hemoglobinopathy gene therapy.

Disclosures: No relevant conflicts of interest to declare.

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