E-MTAB-890 - A CpG mutational hotspot in a ONECUT (HNF6) binding site accounts for the prevalent variant of Hemophilia B Leyden

Status
Released on 6 March 2013, last updated on 4 June 2014
Organism
Homo sapiens, Mus musculus
Samples (8)
Protocols (4)
Description
Hemophilia B, or the 'Royal Disease', arises from mutations in the Coagulation Factor IX (F9) gene. Mutations within the F9 promoter are associated with a remarkable form of the disease, termed Hemophilia B Leyden, in which symptoms ameliorate after puberty. Mutations at the -5/-6 site account for the majority of Leyden cases, and have been postulated to disrupt the binding of a transcriptional activator, the identity of which has remained elusive for more than twenty years. Here we show that the ONECUT transcription factors (ONECUT1/HNF6 and ONECUT2/HNF6B) bind to the -5/-6 site. The various Hemophilia B Leyden mutations that have been reported in this site inhibit ONECUT binding to varying degrees that correlate well with their associated clinical severities. In addition, expression of F9 is crucially dependent on ONECUT factors in vivo and as such, mice that are deficient in either ONECUT1, ONECUT2 or both, exhibit depleted levels of F9. Taken together, our findings establish the ONECUT transcription factors as the missing regulators of Hemophilia B Leyden that operate through the -5/-6 site.
Experiment types
ChIP-seq, ChiP-seq, binding site identification, in vivo, species
Contacts
Margus Lukk <margus.lukk@cruk.cam.ac.uk>, Alister PW Funnell, Benoit Ballester, Duncan T Odom, Frederic Lemaigre, Jon G Burdach, Ka Sin Mak, Kathryn M Stowell, Merlin Crossley <m.crossley@unsw.edu.au>, Michael D Wilson, Natisha Magan, Paul Flicek, Richard CM Pearson
Citations
A CpG mutational hotspot in a ONECUT binding site accounts for the prevalent variant of hemophilia B Leyden. Funnell AP, Wilson MD, Ballester B, Mak KS, Burdach J, Magan N, Pearson RC, Lemaigre FP, Stowell KM, Odom DT, Flicek P, Crossley M. :460-467 (2013), Europe PMC 23472758
A CpG mutational hotspot in a ONECUT binding site accounts for the prevalent variant of Hemophilia B Leyden. Alister P. W. Funnell, Michael D. Wilson, Benoit Ballester, Ka Sin Mak, Jon G. Burdach, Natisha Magan, Richard C. M. Pearson, Frederic Lemaigre, Kathryn M. Stowell, Duncan T. Odom, Paul Flicek, Merlin Crossley.
MINSEQE
Exp. designProtocolsVariablesProcessedSeq. reads
Files
Investigation descriptionE-MTAB-890.idf.txt
Sample and data relationshipE-MTAB-890.sdrf.txt
Links