Gene coexpression network topology of cardiac development, hypertrophy, and failure.
BACKGROUND
Network analysis techniques allow a more accurate reflection of underlying systems biology to be realized than traditional unidimensional molecular biology approaches. Using gene coexpression network analysis, we define the gene expression network topology of cardiac hypertrophy and failure and the extent of recapitulation of fetal gene expression programs in failing and hypertrophied adult myocardium.


RESULTS
We assembled all myocardial transcript data in the Gene Expression Omnibus (n=1617). Because hierarchical analysis revealed species had primacy over disease clustering, we focused this analysis on the most complete (murine) dataset (n=478). Using gene coexpression network analysis, we derived functional modules, regulatory mediators, and higher-order topological relationships between genes and identified 50 gene coexpression modules in developing myocardium that were not present in normal adult tissue. We found that known gene expression markers of myocardial adaptation were members of upregulated modules but not hub genes. We identified ZIC2 as a novel transcription factor associated with coexpression modules common to developing and failing myocardium. Of 50 fetal gene coexpression modules, 3 (6%) were reproduced in hypertrophied myocardium and 7 (14%) were reproduced in failing myocardium. One fetal module was common to both failing and hypertrophied myocardium.


CONCLUSIONS
Network modeling allows systems analysis of cardiovascular development and disease. Although we did not find evidence for a global coordinated program of fetal gene expression in adult myocardial adaptation, our analysis revealed specific gene expression modules active during both development and disease and specific candidates for their regulation.
Department of Internal Medicine and the Division of Cardiovascular Medicine, Stanford Hospital and Clinics, and Stanford University School of Medicine, Stanford, CA 94305, USA.
Frederick E
FE
Dewey
Marco V
MV
Perez
Matthew T
MT
Wheeler
Clifton
C
Watt
Joshua
J
Spin
Peter
P
Langfelder
Steve
S
Horvath
Sridhar
S
Hannenhalli
Thomas P
TP
Cappola
Euan A
EA
Ashley
D000328:Adult; D000818:Animals; D006332:Cardiomegaly / Q000196:embryology* / Q000235:genetics*; D017124:Conserved Sequence / Q000235:genetics; D030541:Databases, Genetic; D005333:Fetus / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks / Q000235:genetics*; D006321:Heart / Q000196:embryology*; D006333:Heart Failure / Q000196:embryology* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism
D014157:Transcription Factors