A GWAS sequence variant for platelet volume marks an alternative DNM3 promoter in megakaryocytes near a MEIS1 binding site

Blood. 2012 Dec 6;120(24):4859-68. doi: 10.1182/blood-2012-01-401893. Epub 2012 Sep 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism*
  • Cell Line, Tumor
  • Cell Lineage / genetics
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Dynamin III / genetics*
  • Gene Expression
  • Genetic Variation
  • Genome, Human / genetics*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Hydrazones / pharmacology
  • Megakaryocytes / metabolism*
  • Mice
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Platelet Count
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Transcription Initiation Site
  • Transcription, Genetic

Substances

  • Homeodomain Proteins
  • Hydrazones
  • MEIS1 protein, human
  • Meis1 protein, mouse
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide
  • Neoplasm Proteins
  • Dynamin III