CpG-depleted promoters harbor tissue-specific transcription factor binding signals--implications for motif overrepresentation analyses.
Motif overrepresentation analysis of proximal promoters is a common approach to characterize the regulatory properties of co-expressed sets of genes. Here we show that these approaches perform well on mammalian CpG-depleted promoter sets that regulate expression in terminally differentiated tissues such as liver and heart. In contrast, CpG-rich promoters show very little overrepresentation signal, even when associated with genes that display highly constrained spatiotemporal expression. For instance, while approximately 50% of heart specific genes possess CpG-rich promoters we find that the frequently observed enrichment of MEF2-binding sites upstream of heart-specific genes is solely due to contributions from CpG-depleted promoters. Similar results are obtained for all sets of tissue-specific genes indicating that CpG-rich and CpG-depleted promoters differ fundamentally in their distribution of regulatory inputs around the transcription start site. In order not to dilute the respective transcription factor binding signals, the two promoter types should thus be treated as separate sets in any motif overrepresentation analysis.
Roider
Helge G
HG
Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin. roider@molgen.mpg.de
Lenhard
Boris
B
Kanhere
Aditi
A
Haas
Stefan A
SA
Vingron
Martin
M
D001665:Binding Sites; D018899:CpG Islands; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*
D014157:Transcription Factors