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Growth retardation in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1.

ABSTRACT: Growth deficiency is a characteristic feature of both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), Mendelian disorders of the epigenetic machinery with similar phenotypes but distinct genetic etiologies. We previously described skeletal growth deficiency in a mouse model of KS1 and further established that a Kmt2d -/- chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth deficiency in a mouse model of KS2, Kdm6a tm1d/+. We show that Kdm6a tm1d/+ mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure. Kdm6a tm1d/+ growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generated Kdm6a -/- chondrogenic cell lines. Similar to our prior in vitro model of KS1, we found that Kdm6a -/- cells undergo premature, enhanced differentiation towards chondrocytes compared to Kdm6a +/+ controls. RNA-seq showed that Kdm6a -/- cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously on Kmt2d -/-, Kdm6a -/-, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression between Kmt2d -/- and Kdm6a -/- at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.

ORGANISM(S): Mus musculus

PROVIDER: GSE262539 | GEO | 2024/03/30

REPOSITORIES: GEO

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Project description:Kabuki Syndrome (KS) is a multisystemic rare disorder, characterized by growth delay, distinctive facial features, intellectual disability, and rarely autism spectrum disorder. This condition is mostly caused by de novo mutations of KMT2D, encoding a catalytic subunit of the COMPASS complex involved in enhancer regulation. KMT2D catalyzes the deposition of histone-3-lysine-4 mono-methyl (H3K4Me1) that marks active and poised enhancers. To assess the impact of KMT2D mutations in the chromatin landscape of KS tissues, we have generated patient-derived induced pluripotent stem cells (iPSC), which we further differentiated into neural crest stem cells (NCSC), mesenchymal stem cells (MSC) and cortical neurons (iN). In addition, we further collected blood samples from 5 additional KS patients. To complete our disease modeling cohort we generated an isogenic KMT2D mutant line from human embryonic stem cells, which we differentiated into neural precursor and mature neurons. Micro-electrode-array (MEA)-based neural network analysis of KS iNs revealed an altered pattern of spontaneous network-bursts in a Kabuki-specific pattern. RNA-seq profiling was performed to relate this aberrant MEA pattern to transcriptional dysregulations, revealing that dysregulated genes were enriched for neuronal functions, such as ion channels, synapse activity, and electrophysiological activity. Here we show that KMT2D haploinsufficiency tends to heavily affect the transcriptome of cortical neurons and differentiated tissues while sparing multipotent states, suggesting that KMT2D has a most prevalent role in terminally differentiated cell and activate transcriptional circuitry unique to each cell type. Moreover, thorough profiling of H3K4Me1 unveiled the almost complete uncoupling between this chromatin mark and the regulatory effects of KMT2D on transcription, which is instead reflected by a defect of H3K27Ac. By integrating RNA-seq with ChIP-seq data we defined TEAD and REST as the master effectors of KMT2D haploinsufficiency. Also, we identified a subset of genes whose regulation is controlled by the balance between KMT2D and EZH2 dosage. Finally, we identified the bona fide direct targets of KMT2D in healthy and KS mature cortical neurons and TEAD2 as the main proxy of KMT2D dysregulation in KS. Overall, our study provides the transcriptional and epigenomic characterization of patient-derived tissues as well as iPSCs and differentiated disease-relevant cell types, as well as the identification of KMT2D direct target in cortical neurons, together with the identification of a neuronal phenotype of the spontaneous electrical activity.

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Growth retardation in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1.

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