Comparative promoter analysis allows de novo identification of specialized cell junction-associated proteins.
Shared transcription factor binding sites that are conserved in distance and orientation help control the expression of gene products that act together in the same biological context. New bioinformatics approaches allow the rapid characterization of shared promoter structures and can be used to find novel interacting molecules. Here, these principles are demonstrated by using molecules linked to the unique functional unit of the glomerular slit diaphragm. An evolutionarily conserved promoter model was generated by comparative genomics in the proximal promoter regions of the slit diaphragm-associated molecule nephrin. Phylogenetic promoter fingerprints of known elements of the slit diaphragm complex identified the nephrin model in the promoter region of zonula occludens-1 (ZO-1). Genome-wide scans using this promoter model effectively predicted a previously unrecognized slit diaphragm molecule, cadherin-5. Nephrin, ZO-1, and cadherin-5 mRNA showed stringent coexpression across a diverse set of human glomerular diseases. Comparative promoter analysis can identify regulatory pathways at work in tissue homeostasis and disease processes.
Medizinische Poliklinik, University of Munich, 80336 Munich, Germany.
Clemens D
CD
Cohen
Andreas
A
Klingenhoff
Anissa
A
Boucherot
Almut
A
Nitsche
Anna
A
Henger
Bodo
B
Brunner
Holger
H
Schmid
Monika
M
Merkle
Moin A
MA
Saleem
Klaus-Peter
KP
Koller
Thomas
T
Werner
Hermann-Josef
HJ
Gröne
Peter J
PJ
Nelson
Matthias
M
Kretzler
D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D006801:Humans; D007365:Intercellular Junctions / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D010750:Phosphoproteins / Q000235:genetics; D050199:Podocytes / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051381:Rats; D014157:Transcription Factors / Q000235:genetics*; D014714:Vertebrates; D062826:Zonula Occludens-1 Protein; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D008565:Membrane Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D062826:Zonula Occludens-1 Protein; D000099152:Cadherin 5; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; C569044:Tjp1 protein, rat; C113267:nephrin