Transcriptional dysregulation of human genes : mechanisms and pathophysiology in hereditary hematological disorders
(1996)
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- Authors
- Supervisors
- Rousseau, Guy
- Abstract
- Gene expression can be regulated at the level of RNA processing, RNA stability, translational control or posttranslational modifications. Still, transcription is the major point of regulation. Cell homeostasis, proliferation and differentiation are regulated by signal transduction pathways through which physiologic stimuli induce specific adaptive responses that may involve quantitative and (or) qualitative changes in gene expression. The aim of this thesis was to show how the study of transcription factors and of their binding sites in DNA provides insight into the molecular mechanisms underlying several hereditary haematological diseases. The presentation is divided in three chapters. <BR> We first present a review of the various levels at which transcription is regulated. Transcriptional regulation is a complex mechanism based on the binding of trans-acting proteins (transcription factors) to their cognate cis-acting DNA sequences (binding sites). We discuss how DNA-protein and protein-protein interactions govern transcriptional regulation and how these processes also depend on chromatin organization. <BR> In the second part of this thesis, we present our contribution to the understanding of the transcriptional regulation of glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency is the most common enzymopathy in humans, resulting in a variety of hemolytic syndromes. Transcribed in all cell types, the G6PD gene is a member of the family of the housekeeping genes. The aim of our work was to delineate, in the promoter region, the cis-acting sequences bind to these regulatory elements. We have delineated the core promoter activity to a fragment extending for -147 to +45 relative to the cap site. All this activity could be assigned to two GC boxes which bond Sp1-like and AP-2-lik proteins. Mutagenesis experiments showed that a single mutation in one of the two GC boxes abolished 60% of promoter activity in HepG2 cells whereas a double mutation virtually abolished that activity in HeLa cells. These data suggests that promoter mutations can have dramatic effects on transcription, even in a context of seemingly redundant cis-acting sequences. This may be relevant not only for the G6PD gene but also for other housekeeping genes. <BR> In the third chapter we review the current knowledge on the transcriptional regulation of the globin genes. These genes are characterized by a tissue- and developmental stage-specific expression. The complex transcriptional mechanisms involved in their regulation provide interesting insights in the pathophysiology of several haemoglobin diseases such as β and α thalassemias. We also discuss the molecular transcriptional defects associated with hemophilia B Leyden and with a rare type of microcytic anemia. <BR> The examples chosen illustrate how molecular biology can pave the way to a better treatment of haematological disorders
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Citations
Philippe, M. (1996). Transcriptional dysregulation of human genes : mechanisms and pathophysiology in hereditary hematological disorders. https://hdl.handle.net/2078.5/111592