Date post: | 22-Jan-2018 |
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Science |
Upload: | y-h-taguchi |
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Identification of aberrant gene expression Identification of aberrant gene expression associated with aberrant promoter associated with aberrant promoter
methylation in primordial germ cells methylation in primordial germ cells between E13 and E16 rat F3 generation between E13 and E16 rat F3 generation
vinclozolin lineagevinclozolin lineage
Yh. Taguchi Department of Physics
Chuo UniversityTokyoJapan
http://www.biomedcentral.com/14712105/16/S18/S16/http://www.biomedcentral.com/14712105/16/S18/S16/
1. What is PCA based unsupervisedunsupervised FE?
2. What is transigenetational epigenetics?
3. Comparison of primordial germ cells between E13 and E16 rat F3 generation vinclozolin lineage and biological validations of obtained gene set
4. Summary
What is PCA based unsupervisedunsupervised FE?
N features
Categorical multiclasses
In contrast to usual usage of PCA, not samples but features are embedded into Q dimensional space.
PC
A
PC1
samples
M samplesN × M Matrix X (numerical values)
PC2
PC1 ++ ++ +
+++
++ ++ ++
+
No distinction between classes
Synthetic example
10 samples10 samples
90 features 10 featuresN(0)N()
[N()+N(0)]/2
+:Top 10 outliersThus, extracting outliers selects features distinct between two classes in an unsupervised way.Accuracy:(100 trials)Accuracy:(100 trials) 89.5% ( 52.6% (
PC1
PC2
Normal μ:mean Distribution ½ :SD
The First example:Transgenerational Epigenetics (TGE)
Phenotype transfers between generations without DNA modification
(also focused in “Cell Best of 2014Cell Best of 2014”)
F3 generation of F0 pregnant female exposed to endocrine disruptor
F0♀F1♂ F2
F3Abnormalities without inherited DNA exposed to endocrine disruptor?
Yes!・ male infertility (GuerreroBosagna, PLoS ONE 2013)・ anxiety behavior (Skinner, PLoS ONE, 2008)・ mate preference (Skinner, BMC Genom., 2013)・ various diseases (Anway, Endocrinology, 2006)
(on prostate, kidney, immune system, testis, and tumor development)
・ reprogramming of primordial germ cells (Skinner, PLoS ONE, 2013)・ stress responses ( Crews, PNAS, 2012)
However, understanding how TGE takes place still lacks.
Authors' conclusion : “A comparison between the germ cell differential DNA methylation regions and the differentially expressed genes indicated no significant overlap”Significant overlaps observed would be Significant overlaps observed would be interesting....interesting....
Skinner, PLoS ONE, 2013:Primordial germ cell in F3 generation at E13 and E16, gene expression/promoter methylation
F2♀F3
N'' com
mon
genes
FeatureExtraction
N' g ene s
FeatureExtraction
Promoter methylation
Vinclozolin treatedControl
E13 E16 E13 E16
Gene expression
Vinclozolin treatedControl
E13 E16 E13 E16
Our strategy.....Our strategy.....
N' ←→ N'' PP
Total N genes
N〜104
Results.....Results.....
P=0.05
Ttest based feature selectionsTtest based feature selections
No overlaps(N' 300)≦
N〜104Results.....Results.....
P=0.05
limma based feature selectionslimma based feature selections
N''=33 genes with RefSeq ID
No significant enrichments of GO BP, GO CC, GO MF, KEGG pathway, or PPI
using DAVID, TargetMine, g:profiler, or STRING
N〜104
Results.....Results.....
P=0.05
SAM based feature selectionsSAM based feature selections
N''=30 genes with RefSeq ID
P=102
No significant enrichments of GO BP, GO CC, GO MF, KEGG pathway, or PPI
using DAVID, TargetMine, g:profiler, or STRING
N〜104
Results.....Results.....
P=0.05
P=103
P=102
PCA based PCA based unsupervisedunsupervised FE FE
N''=48 genes with RefSeq ID
multiple significant enrichments of GO BP, GO MF, using DAVID and g:profiler
Seven PPIs (P=0.05) detected by STRING
N〜104
Results.....Results.....
P=0.05
P=103
P=102
PCA based PCA based unsupervisedunsupervised FE FE
N''=179 genes with RefSeq ID
DAVIDDAVID
g:profilerg:profiler
TargetMineTargetMine
We further validated that 22 genes among 48 genes selected by PCA based unsupervisedunsupervised FE when N'=1000 are related to either kidney, testis, prostate, tumor and immune system whose associated diseases were caused by TGE.
We also proposed that Chemokine signaling pathway as well as LRR proteins are deeply related to TGE.
Because of lack of time, we cannot discuss about it.
Summary・PCA based unsupervisedunsupervised FE identified more genes associated with both differential gene expression and aberrant promoter methylation between E13 and E16 rat F3 generation vinclozolin lineage
・ Genes selected by PCA based unsupervisedunsupervised FE were associated with various enrichments of biological terms/concepts while none were associated with those selected by ttest, limma, or SAM based FE.
・ These suggested definitely the superiority of unsupervisedunsupervised method toward supervised methods.
This study was supported by
Chuo university joint research grant “In silico drug discovery using FAMS”
and
KAKENHI “Initiative for HighDimensional Datadriven Science through Deepening of
Sparse Modeling”