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Regulation of monoamine oxidase A by the SRY gene on the Y chromosome

Jason B. Wu^*, Kevin Chen^*, Yunmin Li, Yun-Fai Chris Lau and Jean C. Shih^*,,1

^* Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, and

Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; and

Department of Medicine, Veterans Affairs Medical Center, University of California, San Francisco, California, USA

¹ Correspondence: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave., PSC 518, Los Angeles, CA 90089-9121, USA. E-mail: jcshih{at}usc.edu

Monoamine oxidase A (MAO A), encoded by the X chromosome, catalyzes the oxidative deamination of monoamine neurotransmitters, such as serotonin, and plays a critically important role in brain development and functions. Abnormal MAO A 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 these disease processes is unclear. Recently, we found that MAO A was a putative target gene directly regulated by a transcription factor encoded by the sex-determining region Y (SRY) gene located on the Y chromosome. We demonstrated that SRY activates both MAO A-promoter and catalytic activities in a human male neuroblastoma BE(2)C cell line. A functional SRY-binding site in the MAO A core promoter was identified and validated by electrophoretic mobility shift and chromatin immunoprecipitation (ChIP) analyses. Coimmunoprecipitation and ChIP assays showed that SRY and Sp1 form a transcriptional complex and synergistically activate MAO A transcription. This is the first study demonstrating that the Y-encoded 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.—Wu, J. B., Chen, K., Li, Y., Lau, Y.-F. C., Shih, J. C. Regulation of monoamine oxidase A by the SRY gene on the Y chromosome.

Key Words: sex-determining region Y gene • transcriptional activation • sexual dimorphism • X chromosome gene • promoter regulation • Sp1 coactivation