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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 4

Top GO functions unique to either Ccm1/Krit1 or Ccm3/Pdcd10 genotypes.

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Top GO functions unique to either Ccm1/Krit1 or Ccm3/Pdcd10 genotypes.
(...
(A) A total of 71 DEGs were identified only in the Ccm1/Krit1 genotype in both mouse BMECs and C. elegans. The gene set enrichment analyses showed 14 enriched GO terms (P < 0.1, FDR corrected) in Ccm1/Krit1 related to DNA repair, angiogenesis, microtubule functions, and magnesium ion binding. (B) Eleven DEGs were identified only in the Ccm3/Pdcd10 genotype and were associated with 247 GO functions. The top 18 GO terms were related to fundamental functions for rRNA processing, ribosome biogenesis and structural constituents, protein targeting to endoplasmic reticulum, protein intracellular targeting, and vesicle transportation to a cell membrane. The DEGs were defined as FC ≥ 1.2 and P < 0.05 (FDR corrected). BH, Bcl-2 homology. Gene ratio is reported at the end of each respective GO.

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