title: A GWAS sequence variant for platelet volume marks an alternative DNM3 promoter in megakaryocytes near a MEIS1 binding site.
abstract: We recently identified 68 genomic loci where common sequence variants are associated with platelet count and volume. Platelets are formed in the bone marrow by megakaryocytes, which are derived from hematopoietic stem cells by a process mainly controlled by transcription factors. The homeobox transcription factor MEIS1 is uniquely transcribed in megakaryocytes and not in the other lineage-committed blood cells. By ChIP-seq, we show that 5 of the 68 loci pinpoint a MEIS1 binding event within a group of 252 MK-overexpressed genes. In one such locus in DNM3, regulating platelet volume, the MEIS1 binding site falls within a region acting as an alternative promoter that is solely used in megakaryocytes, where allelic variation dictates different levels of a shorter transcript. The importance of dynamin activity to the latter stages of thrombopoiesis was confirmed by the observation that the inhibitor Dynasore reduced murine proplatelet for-mation in vitro.
authors.affiliation: Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge, United Kingdom.
authors.forename: Sylvia T
authors.initials: ST
authors.lastname: Nürnberg
authors.forename: Augusto
authors.initials: A
authors.lastname: Rendon
authors.forename: Peter A
authors.initials: PA
authors.lastname: Smethurst
authors.forename: Dirk S
authors.initials: DS
authors.lastname: Paul
authors.forename: Katrin
authors.initials: K
authors.lastname: Voss
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Thon
authors.forename: Heather
authors.initials: H
authors.lastname: Lloyd-Jones
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Sambrook
authors.forename: Marloes R
authors.initials: MR
authors.lastname: Tijssen
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Italiano
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Berthold
authors.initials: B
authors.lastname: Gottgens
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D034286:Dynamin III / Q000235:genetics*; D015870:Gene Expression; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D008533:Megakaryocytes / Q000378:metabolism*; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010976:Platelet Count; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; D006835:Hydrazones; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D009363:Neoplasm Proteins; D034286:Dynamin III