PDGFRA transcriptional regulation in human physiology and disease

Abstract

Gene transcription is regulated by specific DNA sequences surrounding and within genes, so-called cis-acting factors, such as the promoter. Transcription factors or trans-acting factors, bind to these regulatory DNA elements in a sequence specific manner to influence the rate of transcription. Consequently, sequence variation in regulatory DNA elements, referred to as DNA polymorphisms, may alter protein binding and thus transcription of neighboring genes, and subsequently may also influence susceptibility to diseases. The gene encoding the platelet-derived growth factor receptor-alpha (PDGFRA) has been associated with a number of pathological conditions, such as neural tube defects (spina bifida) and various cancers including gliomas. The studies described in this thesis were undertaken to identify both cis- and trans-acting factors that regulate PDGFRA transcription and to determine their involvement in gliomas and NTDs. We identified ten polymorphisms in the human PDGFRA promoter, which together form five haplotypes: H1, H2alpha, H2beta, H2gamma and H2delta, of which H1and H2alpha are the most common. H1 mediates low, while H2alpha mediates high transcriptional activity. Our results indicate that this difference in activity can partly be regulated at the epigenetic level. From several case-control studies it appeared the low activity haplotype H1 was overrepresented in spina bifida cases, while it was underrepresented in glioblastoma cases. This suggests that low PDGFRA expression predisposes to neural tube defects, while at the same time protecting against gliomas. Furthermore, PDGFRA haplotypes appeared to differentially interact with maternal nutritional factors in predisposition to spina bifida, and also affected body growth. Finally, we identified a number of PDGFRA upstream regulators, some of which themselves have been directly associated with NTDs