Thomas Maniatis

Columbia University

Primary Section: 41, Medical Genetics, Hematology, and Oncology
Secondary Section: 21, Biochemistry
Membership Type: Member (elected 1985)

Research Interests

We are interested in studying the mechanisms involved in the regulation of RNA transcription and pre-messenger RNA splicing. Our studies of transcription are focused on the question of how eukaryotic genes are activated in response to extracellular signals or virus infection. We have chosen the human interferon-b gene and Drosophila immune response genes to approach this question. We have characterized the structure and function of regulated transcriptional enhancers and promoters, and analyzed the synergistic interactions between multiple transcriptional activator proteins that specifically associate with these elements. The goal of these studies is to understand how multiprotein transcriptional enhancer complexes are assembled, and how they function to activate or repress gene transcription. We have also studied the signal transduction pathways leading to the activation of the interferon-b gene and Drosophila immune response genes. These studies led to the discovery that regulated proteolysis mediated by the ubiquitin-proteasome pathway plays a critical role in the activation of transcriptional activator proteins required for both pathways. Our studies of pre-mRNA splicing are directed toward understanding how alternative splicing is regulated, and we have chosen the Drosophila doublesex gene to study this problem. We have found that the female-specific splicing pattern of doublesex pre-mRNA is controlled by a splicing enhancer that activates an upstream 3' splice site. This enhancer contains multiple regulatory elements that are specifically recognized by RNA binding proteins that interact with each other and with the enhancer to form a complex that recruits general splicing factors to the adjacent female-specific 3' splice site. We are currently studying the mechanism of this process and the structure of the multiprotein splicing enhancer complex.

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