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Abnormal hypoxia responses in a Kabuki syndrome chondrocyte model

Sara Þöll Halldórsdóttir, Hans Tómas Björnsson

Introduction: Kabuki syndrome (KS) is Mendelian disorder of the epigenetic machinery primarily caused by heterozygous loss of function mutations in the histone methyltransferase KMT2D. Growth retardation is a key phenotype and found in majority of individuals with KS. Prior work has revealed that a Kmt2d-deficient chondrocyte precursor cell model has an accelerated rate of differentiation resulting in premature maturation of chondrocytes. Hypoxia has previously been shown to be important physiological element in bone development, and we hypothesize that KMT2D deficiency impairs hypoxia responses leading to alteration in differentiation rate.

Methods: Murine chondrocyte cell line ATDC5 with or without deletion of Kmt2d were differentiated in vitro in normoxic (20% O2) and hypoxic (1% O2) conditions. Differentiation rate was quantified with Alcian Blue staining. To measure hypoxia response, we performed luciferase reporter assay and immunofluorescence staining.

Results: Cells that lack KMT2D (Kmt2d-/-) exhibit precocious differentiation in normoxic conditions compared to WT cells (p<0.01) but when differentiation is initiated under hypoxia, Kmt2d-/- cells fail to transition to hypertrophic state, resulting in no difference compared to WT cells (ns). When Kmt2d-/- cells are kept in hypoxia, they have higher expression of Hif1a (p<0.01) but fail to activate transcription of hypoxia response genes due to decreased HIF1A nuclear translocation (p<0.0001) compared to WT cells. Conclusions: Our results indicate that hypoxia can inhibit premature hypertrophy of Kmt2d-/- cells and suggests a novel role for KMT2D where it is not only a histone methyltransferase but also plays a part in nuclear import of HIF1A.


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