Transcriptional features of genomic regulatory blocks.
BACKGROUND
Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region. The target genes are most often transcription factors involved in embryonic development and differentiation. GRBs often contain extensive gene deserts, as well as additional 'bystander' genes intertwined with HCNEs but whose expression and function are unrelated to those of the target gene. The tight regulation of target genes, complex arrangement of regulatory inputs, and the differential responsiveness of genes in the region call for the examination of fundamental rules governing transcriptional activity in GRBs. Here we use extensive CAGE tag mapping of transcription start sites across different human tissues and differentiation stages combined with expression data and a number of sequence and epigenetic features to discover these rules and patterns.


RESULTS
We show evidence that GRB target genes have properties that set them apart from their bystanders as well as other genes in the genome: longer CpG islands, a higher number and wider spacing of alternative transcription start sites, and a distinct composition of transcription factor binding sites in their core/proximal promoters. Target gene expression correlates with the acetylation state of HCNEs in the region. Additionally, target gene promoters have a distinct combination of activating and repressing histone modifications in mouse embryonic stem cell lines.


CONCLUSIONS
GRB targets are genes with a number of unique features that are the likely cause of their ability to respond to regulatory inputs from very long distances.
Akalin
Altuna
A
Computational Biology Unit, Bergen Center for Computational Science, and Sars Centre for Marine Molecular Biology, University of Bergen, 5008 Bergen, Norway.
Fredman
David
D
Arner
Erik
E
Dong
Xianjun
X
Bryne
Jan Christian
JC
Suzuki
Harukazu
H
Daub
Carsten O
CO
Hayashizaki
Yoshihide
Y
Lenhard
Boris
B
D000107:Acetylation; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D017124:Conserved Sequence; D018899:CpG Islands; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D024363:Transcription Initiation Site; D014158:Transcription, Genetic / Q000235:genetics*