Assaying the regulatory potential of mammalian conserved non-coding sequences in human cells.
BACKGROUND
Conserved non-coding sequences in the human genome are approximately tenfold more abundant than known genes, and have been hypothesized to mark the locations of cis-regulatory elements. However, the global contribution of conserved non-coding sequences to the transcriptional regulation of human genes is currently unknown. Deeply conserved elements shared between humans and teleost fish predominantly flank genes active during morphogenesis and are enriched for positive transcriptional regulatory elements. However, such deeply conserved elements account for <1% of the conserved non-coding sequences in the human genome, which are predominantly mammalian.


RESULTS
We explored the regulatory potential of a large sample of these 'common' conserved non-coding sequences using a variety of classic assays, including chromatin remodeling, and enhancer/repressor and promoter activity. When tested across diverse human model cell types, we find that the fraction of experimentally active conserved non-coding sequences within any given cell type is low (approximately 5%), and that this proportion increases only modestly when considered collectively across cell types.


CONCLUSIONS
The results suggest that classic assays of cis-regulatory potential are unlikely to expose the functional potential of the substantial majority of mammalian conserved non-coding sequences in the human genome.
Attanasio
Catia
C
Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, 1211, Geneva 4, Switzerland. Catia.Attanasio@medecine.unige.ch
Reymond
Alexandre
A
Humbert
Richard
R
Lyle
Robert
R
Kuehn
Michael S
MS
Neph
Shane
S
Sabo
Peter J
PJ
Goldy
Jeff
J
Weaver
Molly
M
Haydock
Andrew
A
Lee
Kristin
K
Dorschner
Michael
M
Dermitzakis
Emmanouil T
ET
Antonarakis
Stylianos E
SE
Stamatoyannopoulos
John A
JA
D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence / Q000235:genetics*; D019143:Evolution, Molecular; D016678:Genome; D015894:Genome, Human; D006801:Humans; D051379:Mice; D012045:Regulatory Sequences, Nucleic Acid