In vivo deletion of a GWAS-identified Myb distal enhancer acts on Myb expression, globin switching, and clinical erythroid parameters in β-thalassemia
Genome-wide association studies (GWAS) have identified numerous genetic variants linked to human diseases, mostly located in non-coding regions of the genome, particularly in putative enhancers. However, functional assessment of the non-coding GWAS variants has progressed at slow pace, since the functions of the vast majority of genomic enhancers have not been defined, impeding interpretation of disease-susceptibility variants. The HBS1L-MYB intergenic region harbors multiple SNPs associated with clinical erythroid parameters, including fetal hemoglobin levels, a feature impacting disease severity of beta-hemoglobinopathies such as sickle cell anemia and beta-thalassemia. HBS1L-MYB variants cluster in the vicinity of several MYB enhancers, altering MYB expression and globin switching. We and others have highlighted the conserved human MYB - 84kb enhancer, known as the - 81kb enhancer in the mouse, as likely candidate linked to these traits. We report here the generation of a Myb - 81kb enhancer knock-out mouse model, and shed light for the first time on its impact on steady state erythropoiesis and in beta-thalassemia in vivo.
Authors
- Ruud Jorna
- Alex Maas (ORCID: https://orcid.org/0000-0002-6689-3628)
- Virginie Deleuze (ORCID: https://orcid.org/0000-0001-9872-1946)
- Vilma Barroca
- Charles‐Henri Lecellier (ORCID: https://orcid.org/0000-0002-0229-5434)
- Tharshana Stephen (ORCID: https://orcid.org/0000-0002-6560-656X)
- Mohammad Salma (ORCID: https://orcid.org/0000-0002-3648-1809)
- Éric Soler (ORCID: https://orcid.org/0000-0003-0521-7463)
- Marie-Laure Arcangeli (ORCID: https://orcid.org/0000-0002-1726-1472)
- Charlotte Andrieu‐Soler (ORCID: https://orcid.org/0000-0002-3287-6117)
- F. Grosveld
- Cédric Orfeo
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Université Paris Cité (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Institut Gustave Roussy (FR)
- Erasmus MC (NL)
- Laboratory of Excellence GR-Ex (FR)
- CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR)
- Laboratoire d'Informatique, de Robotique et de Microélectronique de Montpellier (FR)
- Institut de Recherche en Cancérologie de Montpellier (FR)
- Institut Regional du Cancer de Montpellier (FR)
- Erasmus University Rotterdam (NL)
Publication Details
- Journal
- Scientific Reports
- Published
- 2025-03-15
- DOI
- https://doi.org/10.1038/s41598-025-94222-8
- Primary Topic
- Hemoglobinopathies and Related Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Infrastructures en Biologie Santé et Agronomie
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Ligue Contre le Cancer
- Institut National Du Cancer
- Direction Générale de l’offre de Soins
- Laboratoire d'Excellence EpiGenMed