Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2021
Erindi/veggspjald / Talk/poster V46
Höfundar / Authors: Sara Þöll Halldórsdóttir (1), Hans Tómas Björnsson (1,2,3)
Starfsvettvangur / Affiliations: 1. Laboratory of Translational Medicine, Faculty of Medicine, University of Iceland; 2. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University ; 3. Department of Genetics and Molecular Medicine, Landspítali
Kynnir / Presenter: Sara Þöll Halldórsdóttir
Kabuki syndrome 1 (KS1) is a Medelian disorder of the epigenetic machinery caused by heterozygous loss of function (LOF) mutations in the Lysine Methyltransferase 2D (Kmt2d). Individuals with KS demonstrate intellectual disability, growth retardation and distinct facial features. Prior work suggested that KS mouse models have shorter bones with expanded growth plates and smaller dentate gyrus compared to WT. Since chondrocytes and neurons differentiate in hypoxic condition and hypoxia is one of the signals that regulates proliferation and differentiation, we hypothesized that abnormal hypoxia responses mediate phenotypes in these cells. A mouse chondrocyte cell line ATDC5 with LOF mutation in the SET domain within Kmt2d were differentiated in vitro under three oxygen levels (1%, 5% and 10%) and compared to differentiation under normoxic conditions (20%). Differentiation rate was quantified with Alcian Blue staining and levels of chondrocyte markers. In normoxia Kmt2dR5551/- and Kmt2d-/- cells demonstrate increased differentiation rate, however, this was rescued by hypoxia but also had some effects on WT cells. Sc-RNA sequencing reveals an expansion in cellular populations expressing genes that encode matrix proteins as well as revealing that abnormal differentiation occurs at the earliest steps of differentiation. Finally, a Seahorse assay indicates abnormal mitochondrial respiration. Together, our data suggest that our cellular phenotype originates early in differentiation and may be caused by abnormal hypoxia responses in the context of generalized metabolic disruption.