Gender Differences in Human Diseases
Why autism affects boys more often than girls?
The incidence of autism is about 1 in 150 among children of North America and Europe. Beside a few pervasive disorders, the eitologies of autism are still uncertain. Autistic children could be generally divided into two groups, a syndromic (complex) group and a high functioning (essential) group. The sex ratio is close to about 1:1 for the syndromic group while there is a prevalence of boys over girls among children of the high-functioning group. The sex ratio could be as high as 10:1 in boys to girls. Currently, such sexual dimorphism in manifestation of autistic traits among the latter group is unknown.
We postulate that genes on the Y chromosome could be ectopically dysregulated during neurogenesis, exerting sutle differences in cognitive development, thereby resulting in sexually dimorphic cognitive circuitry and autistic behaviors. Our research in this area focuses on identifying the putative Y chromosome gene(s) responsible for such ectopic dysregulation of neurogenic genes important for cognitive development. Current efforts are directed at the sex determining gene (SRY) and the TSPY gene on the Y chromosome, and the TSPY homologue (TSPX) on the X chromosome. In general, advanced molecular genetics, genomics and transgenic mouse strategies are utilized in our studies.
SRY regulation of the X-located monoamine oxidase A gene
Among the genes bound by SRY transcription complexes, numerous neural genes were identified and confirmed to be targets for this Y-encoded transcription factor. We have collaborated with Professor Jean Shih and her colleagues at University of Southern California, we have explored the putative regulation of the monoamine oxidase A (MAOA) gene by SRY. MAOA was initially identified as a target gene for SRY in our ChIP-Chip study. MAO A is encoded by the X chromosome and catalyzes the oxidative deamination of monoamine neurotransmitters such as serotonin and plays a critically important role in brain development and functions. Abnormal MAOA activity has been implicated in several neuropsychiatric disorders, such as depression, autism and attention deficit hyperactivity disorder, which show sexual dimorphism. However, the molecular basis for the disease processes is unclear. Through our collaboration with Dr. Shih and colleagues, we demonstrated that SRY activates both MAOA promoter and catalytic activities in a human male neuroblastoma BE(2)C cell line. A functional SRY-binding site at the MAOA core promoter was identified and validated by electrophoretic mobility shift and chromatin immunoprecipitation (ChIP) analyses. Co-immunoprecipitation and ChIP assays showed that SRY and Sp1 form a transcriptional complex and synergistically activate MAO A transcription. Hence, the present study demonstrated that a Y-located transcription factor SRY is capable of regulating an X-located gene, suggesting a novel molecular mechanism for sexual dimorphism in neural development, brain functions and initiation/progression of neural disorders associated with MAO A dysfunction. This study demonstrates the potential of Y chromosome genes in regulation and/or exertion of sexual dimorphic effects on normal physiology and diseases.
Sex disparity in HBV-associated hepatocellular carcinoma
Hepatocellular carcinoma is a prevalent and deadly cancer among populations chronically infected with hepatitis viruses. In particular, a significant gender disparity with a male to female ratio as high as 4:1 in hepatocelluar carcinoma development is observed among populations chronically infected with the hepatitis B virus. Recently, we demonstrated that the Y-located TSPY gene is preferentially expressed in some hepatocellular carcinoma specimens. Its expression is usually associated with those, such as FOXM1 and cancer stem cell marker, CD133, in hepatocellular carcinomas. Hence, TSPY could predispose susceptible hepatocytes to tumorigenesis associated with HBV infection. Significantly, an X-homologue of TSPY, called TSPX shares significant homology in certain part of TSPY, but diverges at their carboxyl termini. Our studies showed that the carboxyl terminal domain of TSPX could inhibit the cyclin B-CDK1 kinase activities while TSPY, without the carboxyl domain of TSPX, stimulates such cyclin B-CDK1 kinase activities. Hence, TSPX possesses contrasting properties with those of TSPY, and could serve a house-keeping function in modulating proper cell cycle progression and tumor suppressor function. Further, TSPX promotes proteosomal degradation of the putative oncoprotein, HBx, in HBV while TSPY does not. Hence, TSPX is a tumor suppressor for HCC. Accordingly, the Y-located TSPY could contribute to the oncogenic process by disrupting the cell cycle regulation in susceptible hepatocytes while the mutations of the X-located TSPX minimizes its tumor suppression effects, thereby collectively exerting a male preference in hepatocellular carcinoma development in HBV-infected populations.