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Comprehensive transcriptome analysis of cerebral cavernous malformation across multiple species and genotypes
Janne Koskimäki, … , Douglas A. Marchuk, Issam A. Awad
Janne Koskimäki, … , Douglas A. Marchuk, Issam A. Awad
Published February 7, 2019
Citation Information: JCI Insight. 2019;4(3):e126167. https://doi.org/10.1172/jci.insight.126167.
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Research Article Neuroscience Vascular biology

Comprehensive transcriptome analysis of cerebral cavernous malformation across multiple species and genotypes

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Abstract

The purpose of this study was to determine important genes, functions, and networks contributing to the pathobiology of cerebral cavernous malformation (CCM) from transcriptomic analyses across 3 species and 2 disease genotypes. Sequencing of RNA from laser microdissected neurovascular units of 5 human surgically resected CCM lesions, mouse brain microvascular endothelial cells, Caenorhabditis elegans with induced Ccm gene loss, and their respective controls provided differentially expressed genes (DEGs). DEGs from mouse and C. elegans were annotated into human homologous genes. Cross-comparisons of DEGs between species and genotypes, as well as network and gene ontology (GO) enrichment analyses, were performed. Among hundreds of DEGs identified in each model, common genes and 1 GO term (GO:0051656, establishment of organelle localization) were commonly identified across the different species and genotypes. In addition, 24 GO functions were present in 4 of 5 models and were related to cell-to-cell adhesion, neutrophil-mediated immunity, ion transmembrane transporter activity, and responses to oxidative stress. We have provided a comprehensive transcriptome library of CCM disease across species and for the first time to our knowledge in Ccm1/Krit1 versus Ccm3/Pdcd10 genotypes. We have provided examples of how results can be used in hypothesis generation or mechanistic confirmatory studies.

Authors

Janne Koskimäki, Romuald Girard, Yan Li, Laleh Saadat, Hussein A. Zeineddine, Rhonda Lightle, Thomas Moore, Seán Lyne, Kenneth Avner, Robert Shenkar, Ying Cao, Changbin Shi, Sean P. Polster, Dongdong Zhang, Julián Carrión-Penagos, Sharbel Romanos, Gregory Fonseca, Miguel A. Lopez-Ramirez, Eric M. Chapman, Evelyn Popiel, Alan T. Tang, Amy Akers, Pieter Faber, Jorge Andrade, Mark Ginsberg, W. Brent Derry, Mark L. Kahn, Douglas A. Marchuk, Issam A. Awad

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Figure 5

Functional interaction network of DEGs conserved in both mouse BMECs and C. elegans unique to either Ccm1/Krit1 or Ccm3/Pdcd10.

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Functional interaction network of DEGs conserved in both mouse BMECs and...
(A) The functional interaction network analysis of the 71 common DEGs (FC ≥ 1.2; P < 0.05, FDR corrected) identified only in Ccm1/Krit1 models showed that FGFR3, PDGFRA, PLK1, NUP85, and PLCD3 had more than 6 edges. (B) The functional interaction network analysis of the 11 common DEGs (FC ≥ 1.2; P < 0.05, FDR corrected) identified only in the Ccm3/Pdcd10 genotype revealed that RPL21 and RPS18 were the genes with the most edges (more than 6).

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