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Telomere Length Protects Mice from Human Disease Phenotype Caused By Notch1 Haploinsufficiency

ABSTRACT: Diseases caused by gene haploinsufficiency in humans commonly lack a phenotype in mice heterozygous for the orthologous factor, although the source of this discrepancy is unknown. The inability to accurately model human disease in mice impedes the study of complex phenotypes and critically limits the discovery and testing of potential therapeutics. Laboratory mice have longer telomeres (>40 kilobases (kb)) compared to humans (~5-15 kb), potentially protecting them from age-related disease caused by haploinsufficiency. In humans, heterozygous non-sense mutations in the transcription factor, NOTCH1 (N1), lead to severe age-dependent aortic valve (AV) calcification. However, mice heterozygous for N1 do not develop calcific AV disease (CAVD)5. Here, we show that telomere shortening is sufficient to elicit age-dependent cardiac valve disease in N1+/- mice that closely mimics the human disease and that progressive shortening correlates with severity of disease, extending to AV thickening in the neonate. N1 haploinsufficiency led to increased proliferation in valves that further reduced telomere length. Calcified AVs exhibited downregulation of osteoclast factors and upregulation of pro-calcific regulatory nodes concordant with gene network alterations in human N1 heterozygous endothelial cells. Dysregulated genes in valves were enriched for those that have promoters normally contacted by telomere looping. These findings reveal a critical role for telomere length in a mouse model of age-dependent human disease that may have broader implications and provides an in vivo model in which to test therapeutic candidates to prevent or delay the progression of CAVD.

ORGANISM(S): Mus musculus

PROVIDER: GSE83963 | GEO | 2017/08/22

SECONDARY ACCESSION(S): PRJNA327570

REPOSITORIES: GEO

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Project description:E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells; In the study we demonstrated shared gene expression in embryonic heart valve development and Osteoblast progenitor cells. The atrioventricular (AV) valves of the heart develop from undifferentiated mesenchymal endocardial cushions, that later remodel into stratified valves with diversified extracellular matrix (ECM). Because the mature valves express genes associated with osteogenesis and exhibit disease-associated calcification, we hypothesized the existence of shared regulatory pathways active in the remodeling AV valves and in bone progenitor cells. In order to define gene regulatory programs of valvulogenesis relative to osteoblast progenitors, we undertook Affymetrix gene expression profiling analysis of murine embryonic day (E)12.5 AV cushions compared to E17.5 remodeled AV valves (mitral and tri-cuspid) and to pre-osteoblast MC3T3-E1 (subclone4) cells. Overall MC3T3 cells were significantly more similar to E17.5 valves than to E12.5 cushions, supporting the hypothesis that valve remodeling involves the expression of many genes also expressed in osteoblasts. Several transcription factors characteristic of mesenchymal and osteoblast precursor cells, including Twist1 are predominant in E12.5 cushion. Valve remodeling also includes differential regulation of matrix metalloproteinases and their inhibitors as well as characteristic collagen isoform switching. Among the most highly enriched genes during valvulogenesis were members of the small leucine-rich proteoglycan (SLRP) family including Asporin, a known negative regulator of osteoblast differentiation and mineralization. Together, these data support shared gene expression profiles of the remodeling valves and osteoblast bone precursor cells in normal valve development and homeostasis with potential functions in calcific valve disease. Experiment Overall Design: In the study, we hybridized RNA from E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells to Affymetrix MOE430 2 GeneChipÂ® arrays.

Project description:Aims Calcific aortic valve disease (CAVD) is a significant cause of illness and death worldwide. The disease mechanism involves age-associated immuno-osteogenic processes but developmental origins and early disease mechanisms are not fully characterized. Identification of early predictive markers could help optimize therapy decisions and patient follow-up. Methods and Results RNA-sequencing was carried out on human fetal aortic valves at weeks 9, 13, and 22, and adult control, calcified bicuspid (BAV) and tricuspid aortic valves (TAV). K-means clustering was implemented to identify co-expressed gene patterns simultaneously up- and down-regulated over the different conditions. Canonical pathway analysis revealed a predominant immune-metabolic gene signature indicative of ongoing innate and adaptive immune responses, including lymphocyte T-cell metabolic adaptation. Specifically, cytokine and chemokine signalling, cellular migration and proliferation, were all increased in CAVD, while oxidative phosphorylation and protein translation were decreased. Discrete immune-metabolic gene signatures were present at foetal stages and adult controls, indicating that inflammation initiates as soon as the valves are formed and is maintained and amplified during post-natal life. Multiple pathways involved in cellular stress response and neurodegenerative disease were also aberrantly expressed, suggesting that chronic inflammation drives metabolic stress- and age-associated valve pathology in CAVD. Comparing the valve RNA-sequencing dataset with whole blood transcriptomes from asymptomatic individuals with early aortic valve calcification identified a gene signature including the CD28 pathway, highly predictive of patients with CAVD and healthy individuals with moderate levels of aortic valve calcification. Conclusion These data deepen and broaden our understanding of the molecular basis of CAVD, and identify a gene signature for the early detection of aortic valve calcification. Keywords Human foetal valve, CAVD, BAV, inflammation, biomarker, gene signature,PESA

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Telomere Length Protects Mice from Human Disease Phenotype Caused By Notch1 Haploinsufficiency

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