Genetic and epigenetic determinants of hematopoiesis

Genetic and epigenetic determinants of hematopoiesis

Genetic and epigenetic determinants of hematopoiesis

The hematopoietic system provides a good model system to inform interpretation of association studies owing to simple phenotypes at the cellular level; nearly unlimited access to suitable tissue with good ability for in vitro manipulation; suitable model organisms; widespread clinical relevance. We use genetic approaches to identify novel genes and gene variants affecting the development in humans. In work to date, we have discovered nearly ~150 loci affecting variation in blood cell elements through genome-wide association studies. We have further sought to combine genetic discoveries to a host of integrative analyses and functional approaches, including protein-protein interaction networks, in vitro differentiation of HSCs towards red cell and platelet precursors, and silencing experiments in model organisms (fly, zebrafish and mouse). Our results to date support the notion that the regulation of the formation and survival of blood cells in healthy individuals is mediated through a host of previously unknown regulators, prevalently active in the late stages of lineage commitment, and affecting blood cell formation in a prevalently lineage-specific manner. As an extension to this work, we now aim to identify and characterize in greater depth molecular traits underpinning these genetic effects through genome-wide epigenetic and gene expression explorations. This work is part of the EU FP7-funded BLUEPRINT project, which will generate reference genomes and epigenomes of at least 100 specific blood cell types.

Publications

  • A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function.

    Soranzo N, Rendon A, Gieger C, Jones CI, Watkins NA et al.

    Blood 2009;113;16;3831-7

  • A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium.

    Soranzo N, Spector TD, Mangino M, Kühnel B, Rendon A et al.

    Nature genetics 2009;41;11;1182-90

  • Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.

    Ganesh SK, Zakai NA, van Rooij FJ, Soranzo N, Smith AV et al.

    Nature genetics 2009;41;11;1191-8

  • Maps of open chromatin guide the functional follow-up of genome-wide association signals: application to hematological traits.

    Paul DS, Nisbet JP, Yang TP, Meacham S, Rendon A et al.

    PLoS genetics 2011;7;6;e1002139

  • New gene functions in megakaryopoiesis and platelet formation.

    Gieger C, Radhakrishnan A, Cvejic A, Tang W, Porcu E et al.

    Nature 2011;480;7376;201-8

  • Seventy-five genetic loci influencing the human red blood cell.

    van der Harst P, Zhang W, Mateo Leach I, Rendon A, Verweij N et al.

    Nature 2012;492;7429;369-75

  • Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci.

    Paul DS, Albers CA, Rendon A, Voss K, Stephens J et al.

    Genome research 2013;23;7;1130-41

  • Transcriptional diversity during lineage commitment of human blood progenitors.

    Chen L, Kostadima M, Martens JH, Canu G, Garcia SP et al.

    Science (New York, N.Y.) 2014;345;6204;1251033