| Popis: |
Transcription factors that regulate the expression of neuronal genes remain incompletely understood. The focus of my research has been on the function a novel helix-loop-helix transcription factor, Freud-1, which is implicated in the regulation of the 5-HT1A receptor and is genetically linked to non-syndromic mental retardation. Initially, I have characterized the repressor activity of a novel long isoform of human Freud-1 and shown that it is the major isoform expressed in human cells, and that it binds and represses at a specific DNA element in the human serotonin 1 A receptor promoter. I have further identified a new negative regulatory DNA element in the second intron of the dopamine-D2 receptor gene and shown that Freud-1 binds to this element in vitro as well as in chromatin, and mediates repression by this element. Importantly, specific depletion of Freud-1 protein levels resulted in upregulation of dopamine-D2 receptor expression. Additionally, I identified and characterized a functional polymorphism in the dopamine- D2 receptor gene that is located proximal to the repressor element, and which attenuated Freud-1 binding and activity by half. This functional dopamine-D2 receptor gene polymorphism was genetically linked to a well-studied Taq1A polymorphism of unknown function that is associated with addictive disorders. Association analysis did not reveal an association of this polymorphism in patients with major depressive disorder or schizophrenia compared to normal subjects. In summary, I have identified Freud-1 as an important transcription factor involved in regulation of dopamine-D2 receptor gene expression. Altered regulation of Freud-1 could lead to alterations in dopamine-D2 and serotonin 1A receptor expression that could be implicated in mental illness, as well as in cognitive development. |
