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Genetic and transcriptomic analysis of megakaryocytes Kammers, Kai


Aggregation of platelets in the blood on ruptured or eroded atherosclerotic plaques may initiate arterial occlusions causing heart attacks, strokes, and limb ischemia. Understanding the biology of platelet aggregation is important to prevent inappropriate vascular thrombosis. GWAS studies have identified common variants associated with platelet aggregation, but because they are intronic or intergenic, it is not clear how they are linked biologically to platelet function. To examine this, we are funded to produce pluripotent stem cells (iPSCs) from people with informative genotypes, and then derive megakaryocytes (MKs), the precursor cells for anucleate platelets, from the iPSCs to determine patterns of gene transcript expression in the MKs related to specific genetic variants. To this end it is essential that the iPSC-derived MKs retain their genomic integrity during production or expansion. This was examined using three alternative measures of integrity of the MK cell lines: (1) mutation rates comparing parent cell DNA to iPSC cell DNA and onward to the differentiated MK DNA; (2) structural integrity using copy number variation (CNV) on the same; and (3) transcriptomic signatures of the derived MK cells. For the RNASeq data we extracted non- ribosomal RNA from 14 paired iPS and MK cell lines. Looking specifically for genes ‘turned on’ in MKs following differentiation from the iPSCs, we observed the following highly biologically relevant gene sets in the list of top 12 identified: platelet activation immune response, inflammatory response, platelet formation, and regulation of cell proliferation. Most recently, we performed extensive eQTL analyses with megakaryocytes to categorize ‘functional’ relevance of the GWAS-identified determinants of platelet aggregation leveraging the genotype and RNASeq data.

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