Genome-wide detection of a TFIID localization element from an initial human disease mutation.
Eukaryotic core promoters are often characterized by the presence of consensus motifs such as the TATA box or initiator elements, which attract and direct the transcriptional machinery to the transcription start site. However, many human promoters have none of the known core promoter motifs, suggesting that undiscovered promoter motifs exist in the genome. We previously identified a mutation in the human Ankyrin-1 (ANK-1) promoter that causes the disease ankyrin-deficient Hereditary Spherocytosis (HS). Although the ANK-1 promoter is CpG rich, no discernable basal promoter elements had been identified. We showed that the HS mutation disrupted the binding of the transcription factor TFIID, the major component of the pre-initiation complex. We hypothesized that the mutation identified a candidate promoter element with a more widespread role in gene regulation. We examined 17,181 human promoters for the experimentally validated binding site, called the TFIID localization sequence (DLS) and found three times as many promoters containing DLS than TATA motifs. Mutational analyses of DLS sequences confirmed their functional significance, as did the addition of a DLS site to a minimal Sp1 promoter. Our results demonstrate that novel promoter elements can be identified on a genome-wide scale through observations of regulatory disruptions that cause human disease.
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Rockville, MD 20852, USA.
Mary Q
MQ
Yang
Karina
K
Laflamme
Valer
V
Gotea
Clinton H
CH
Joiner
Nancy E
NE
Seidel
Clara
C
Wong
Hanna M
HM
Petrykowska
Jens
J
Lichtenberg
Stephen
S
Lee
Lonnie
L
Welch
Patrick G
PG
Gallagher
David M
DM
Bodine
Laura
L
Elnitski
D017487:Ankyrins / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D016384:Consensus Sequence; D015894:Genome, Human; D006801:Humans; D020014:K562 Cells; D009154:Mutation; D011401:Promoter Regions, Genetic; D013103:Spherocytosis, Hereditary / Q000235:genetics*; D035362:Transcription Factor TFIID / Q000378:metabolism*; D024363:Transcription Initiation Site
C110202:ANK1 protein, human; D017487:Ankyrins; D035362:Transcription Factor TFIID