Transcriptomics,Genomics

Dataset Information

167

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. Overall design: RNA-sequencing of aortic valves dissected from mice WT or heterozygous for Notch1 in the setting of long (Terc WT) or shortened (generation 2 Terc-/-) telomeres

INSTRUMENT(S): Illumina HiSeq 2500 (Mus musculus)

SUBMITTER: Christina Theodoris  

PROVIDER: GSE83963 | GEO | 2017-08-22

SECONDARY ACCESSION(S): PRJNA327570

REPOSITORIES: GEO

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Publications

Long telomeres protect against age-dependent cardiac disease caused by NOTCH1 haploinsufficiency.

Theodoris Christina V CV   Mourkioti Foteini F   Huang Yu Y   Ranade Sanjeev S SS   Liu Lei L   Blau Helen M HM   Srivastava Deepak D  

The Journal of clinical investigation 20170327 5


Diseases caused by gene haploinsufficiency in humans commonly lack a phenotype in mice that are heterozygous for the orthologous factor, impeding the study of complex phenotypes and critically limiting the discovery of therapeutics. Laboratory mice have longer telomeres relative to humans, potentially protecting against age-related disease caused by haploinsufficiency. Here, we demonstrate that telomere shortening in NOTCH1-haploinsufficient mice is sufficient to elicit age-dependent cardiovascu  ...[more]

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