Transcription regulation and human diseases.

Regulation of gene expression is a crucial step in the maintenance of cellular homeostasis. The control of gene expression can occur in multiple steps. The overwhelming majority of regulatory events occur at the level of transcription. To initiate transcription eukaryotic polymerase RNA II requires the close collaboration of a battery of proteins collectively termed transcription factors. Transcription factors are generally divided into two groups: (1) the basal transcription factors which are ubiquitous and recruit the RNA polymerase II multi-protein complex to the minimal promoter; (2) gene-specific transcription factors that activate or repress basal transcription. These proteins bind to regulatory sequences organized in a series of regulatory modules along the DNA. Thus, the molecular basis for transcriptional regulation of gene expression is the binding of transacting proteins (transcription factors) to cis-acting sequences (binding sites). A growing list of human diseases are due to genetic defects in transcription factors. In most cases, mutations in transcription factors lead to pleiotropic effects. Clinical observations can be explained at the molecular level by the fact that these trans-acting factors control the expression of many genes, usually in combination with one or more further activators. In addition, many events that lead to the process of tumourigenesis in leukaemias and in solid tumours implicate overexpression or mutations of transcription factors. This review describes human diseases attributable to mutations in the genes coding for transcription factors or mutations in their cognate binding sites.