Linking disease-associated genes to regulatory networks via promoter organization.
Pathway- or disease-associated genes may participate in more than one transcriptional co-regulation network. Such gene groups can be readily obtained by literature analysis or by high-throughput techniques such as microarrays or protein-interaction mapping. We developed a strategy that defines regulatory networks by in silico promoter analysis, finding potentially co-regulated subgroups without a priori knowledge. Pairs of transcription factor binding sites conserved in orthologous genes (vertically) as well as in promoter sequences of co-regulated genes (horizontally) were used as seeds for the development of promoter models representing potential co-regulation. This approach was applied to a Maturity Onset Diabetes of the Young (MODY)-associated gene list, which yielded two models connecting functionally interacting genes within MODY-related insulin/glucose signaling pathways. Additional genes functionally connected to our initial gene list were identified by database searches with these promoter models. Thus, data-driven in silico promoter analysis allowed integrating molecular mechanisms with biological functions of the cell.
Döhr
S
S
Institute of Experimental Genetics, GSF-National Research Center for Environment and Health Ingolstädter Landstrasse 1, D-85764 Neuherberg, Germany.
Klingenhoff
A
A
Maier
H
H
Hrabé de Angelis
M
M
Werner
T
T
Schneider
R
R
D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D010802:Phylogeny; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods*; D014157:Transcription Factors / Q000378:metabolism
D014157:Transcription Factors