Targeted disruption of the histone lysine 79 methyltransferase Dot1L in nephron progenitors causes congenital renal dysplasia
Autor: | Chao-Hui Chen, Samir S. El-Dahr, Jenny M. Ngo, Yuwen Li, Zubaida Saifudeen, Hongbing Liu, Maria Luisa S. Sequeira-Lopez, Fenglin Wang |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer Research Methyltransferase Regulator Nephron Histones Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Epigenetics Molecular Biology Kidney biology Lysine Histone-Lysine N-Methyltransferase Methyltransferases Nephrons DOT1L DNA Methylation Cell biology 030104 developmental biology medicine.anatomical_structure Histone 030220 oncology & carcinogenesis Histone Methyltransferases biology.protein Homeostasis Research Paper |
Zdroj: | Epigenetics |
ISSN: | 1559-2308 1559-2294 |
DOI: | 10.1080/15592294.2020.1861168 |
Popis: | The epigenetic regulator Dot1, the only known histone H3K79 methyltransferase, has a conserved role in organismal development and homoeostasis. In yeast, Dot1 is required for telomeric silencing and genomic integrity. In Drosophila, Dot1 (Grappa) regulates homoeotic gene expression. Dysregulation of DOT1L (human homologue of Dot1) causes leukaemia and is implicated in dilated cardiomyopathy. In mice, germline disruption of Dot1L and loss of H3K79me2 disrupt vascular and haematopoietic development. Targeted inactivation of Dot1L in principal cells of the mature collecting duct affects terminal differentiation and cell type patterning. However, the role of H3K79 methylation in mammalian tissue development has been questioned, as it is dispensable in the intestinal epithelium, a rapidly proliferating tissue. Here, we used lineage-specific Cre recombinase to delineate the role of Dot1L methyltransferase activity in the mouse metanephric kidney, an organ that develops via interactions between ureteric epithelial (Hoxb7) and mesenchymal (Six2) cell lineages. The results demonstrate that Dot1L(Hoxb7) is dispensable for ureteric bud branching morphogenesis. In contrast, Dot1L(Six2) is critical for the maintenance and differentiation of Six2+ progenitors into epithelial nephrons. Dot1LSix2 mutant kidneys exhibit congenital nephron deficit and cystic dysplastic kidney disease. Molecular analysis implicates defects in key renal developmental regulators, such as Lhx1, Pax2 and Notch. We conclude that the developmental functions of Dot1L-H3K79 methylation in the kidney are lineage-restricted. The link between H3K79me and renal developmental pathways reaffirms the importance of chromatin-based mechanisms in organogenesis. |
Databáze: | OpenAIRE |
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