A Loss of Function Screen of Identified Genome-Wide Association Study Loci Reveals New Genes Controlling Hematopoiesis

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In this manuscript we report on a follow-up study of the GWAS loci associated with the platelet size and number. A GWAS meta-analysis identified 68 genetic loci controlling platelet size and number. Only a quarter of those genes, however, are known regulators of hematopoiesis. To determine function of the remaining genes we performed a medium-throughput genetic screen in zebrafish using morpholinos (MOs) to knock down selected candidate genes. Here, we report on two major findings. First we identified 15 genes (corresponding to 12 human genes) required for distinct stages of specification or differentiation of HSCs in zebrafish. A detailed review of databases and literature revealed limited knowledge about the functional role of Satb1, Rcor1 and Brd3 in hematopoiesis and for the remaining nine genes our work represents the first study on their putative role in hematopoiesis. And secondly, we demonstrate that brd3a is critical for establishing, but not maintaining thrombopoietic compartment. Importantly, our study introduces zebrafish as a model system for functional follow-up of GWAS loci and generates a valuable resource for prioritization of platelet size and number associated genes for future in-depth mechanistic analyses. Following this route of investigation new regulatory molecules of hematopoiesis will be added to critical pathways.

Vyšlo v časopise: A Loss of Function Screen of Identified Genome-Wide Association Study Loci Reveals New Genes Controlling Hematopoiesis. PLoS Genet 10(7): e32767. doi:10.1371/journal.pgen.1004450
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004450

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