β-catenin promoter ChIP-chip reveals potential schizophrenia and bipolar disorder gene network.
Therapeutic concentrations of lithium salts inhibit glycogen synthase kinase 3 beta (GSK3β) and phosphoinositide (PI) signaling suggesting that abnormal activation of these pathways could be a factor in the pathophysiology of bipolar disorder (BD). Involvement of these pathways is also supported by recent genome-wide association studies (GWASs). One way investigators have investigated the molecular basis of BD and the therapeutic action of lithium is by microarray expression studies, since both GSK3β- and PI-mediated signal transduction pathways are coupled to transcriptional activation and inhibition. However, expression profiling has some limitations and investigators cannot use the approach to analyze fetal brain tissue, arguably the most relevant biological structure related to the development of genetically based psychiatric disorders. To address these shortcomings, the authors have taken a novel approach using chromatin immunoprecipitation-enriched material annealed to microarrays (ChIP-chip) targeting genes in fetal brain tissue bound by β-catenin, a transcription factor that is directly regulated by GSK3β. The promoters for 640 genes were found to be bound by β-catenin, many of which are known schizophrenia (SZ), autism spectrum disorder (ASD), and BD candidates, including CACNA1B, NRNG, SNAP29, FGFR1, PCDH9, and nine others identified in recently published GWASs and genome-wide searches for copy number variants (CNVs). The findings suggest that seemingly disparate candidate genes for SZ and BD can be incorporated into a common molecular network revolving around GSK3β/β-catenin signaling. In addition, the finding that a putative lithium-responsive pathway may influence a subgroup of SZ and ASD candidate genes could have therapeutic implications.
Pedrosa
Erika
E
Department of Psychiatry and Behavioral Sciences, Division of Basic Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Shah
Abhishek
A
Tenore
Christopher
C
Capogna
Michael
M
Villa
Catalina
C
Guo
Xingyi
X
Zheng
Deyou
D
Lachman
Herbert M
HM
D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D001921:Brain; D015820:Cadherins / Q000235:genetics; D020864:Calcium Channels, N-Type / Q000235:genetics; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics; D047369:Chromatin Immunoprecipitation / Q000379:methods*; D005260:Female; D005333:Fetus; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007295:Inositol Phosphates / Q000037:antagonists & inhibitors / Q000378:metabolism; D008094:Lithium / Q000378:metabolism / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D000091363:Protocadherins; D050766:Qb-SNARE Proteins / Q000235:genetics; D050767:Qc-SNARE Proteins / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C500545:CACNA1B protein, human; D015820:Cadherins; D020864:Calcium Channels, N-Type; D007295:Inositol Phosphates; C115817:PCDH9 protein, human; D000091363:Protocadherins; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; C432420:SNAP29 protein, human; D051176:beta Catenin; D008094:Lithium; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3