Codanin-1 mutations engineered in human erythroid cells demonstrate role of CDAN1 in terminal erythroid maturation
| Autor: | Zachary C. Murphy, Michael Getman, Ryo Kurita, Kimberly N. Burgos Villar, Laurie A. Steiner, Emily Leshen, Jaquelyn A. Myers, Yukio Nakamura |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Cell division Cell Survival Mutant medicine.disease_cause Article Cell Line 03 medical and health sciences 0302 clinical medicine Erythroid Cells Genetics medicine Humans Histone code Erythropoiesis Molecular Biology Anemia Dyserythropoietic Congenital Glycoproteins Cell Nucleus Gene Editing Mutation biology DNA replication Nuclear Proteins Acetylation Erythroid Hyperplasia Exons Cell Biology Hematology Chromatin Cell biology Histone Code Phenotype 030104 developmental biology Histone 030220 oncology & carcinogenesis biology.protein CRISPR-Cas Systems Protein Processing Post-Translational |
| Zdroj: | Exp Hematol |
| ISSN: | 0301-472X |
| DOI: | 10.1016/j.exphem.2020.09.201 |
| Popis: | The generation of a functional erythrocyte from a committed progenitor requires significant changes in gene expression during a time of hemoglobin accumulation, rapid cell division, and nuclear condensation. Congenital Dyserythropoietic Anemia type I (CDA-I), is an autosomal recessive disease that presents with erythroid hyperplasia in the bone marrow. Erythroblasts in patients with CDA-I are frequently binucleate, have chromatin bridging, and defective chromatin condensation. CDA-1 is most commonly caused by mutations in Codanin-1 (CDAN1). The function of CDAN1 is poorly understood but it is thought to regulate histone incorporation into nascent DNA during cellular replication. The study of CDA-1 has been limited by lack of in vitro models that recapitulate key features of the disease and most studies on CDAN1 function have been done in non-erythroid cells. To model CDA-I we generated HUDEP2 mutant lines with deletion or mutation of R1042 of CDAN1, mirroring mutations found in CDA-1 patients. CDAN1 mutant cell lines had decreased viability, increased intercellular bridges, and binucleate cells. Further, they had alterations in histone acetylation associated with prematurely elevated erythroid gene expression, including gamma-globin. Together, these data imply a specific functional role for CDAN1, specifically R1042 on exon 24, in the regulation of DNA replication and organization during erythroid maturation. Most importantly, generation of models with specific patient mutations, such as R1042, will provide further mechanistic insight into CDA-I pathology. |
| Databáze: | OpenAIRE |
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