Functional Genomics and Insights into Trypanosoma cruzi Gene Expression Regulation

Abstract

Abstract:The regulation of gene expression in trypanosomatids is predominantly post-transcriptional. Polycistronic transcripts are processed by the addition of a common 5'-spliced leader and polyadenylation. However, the processed mRNAs are not necessarily functionally related, suggesting the existence of mechanisms for the degradation or storage of untranslatable mRNAs. Determination of the TriTryps (Leishmania major, Trypanosoma brucei and Trypanosoma cruzi) genome sequences has allowed the identification of genes encoding potential regulatory proteins. This review discusses some of the mechanisms and regulatory elements involved in cytoplasmic gene expression regulation in Trypanosoma cruzi. We also discuss how functional genomic tools have contributed toward determining the role played by RNA binding protein complexes, supporting the concept of "post-transcriptional RNA operons" or "RNA regulons". This suggests the existence of interconnected regulatory networks in the parasite, in which RNA granules act as protagonists in cytoplasmic mRNA metabolism.Keywords: Trypanosoma cruzi, RNA binding protein, gene expression regulation, functional genomics. TRANSCRIPTION OF MESSENGER RNATrypanosoma cruzi (T. cruzi) is the protozoan parasite causing Chagas disease, a major disease endemic to Latin America. It belongs to the Kinetoplastida order and has a complex life cycle, alternating between insect vectors and mammalian hosts. In both hosts, T. cruzi goes through morphological and functional changes, creating non-infective and infective forms. Those changes resulted from selective adaptation and are the major consequence of differential gene expression. Being a single cell, it needs to quickly regulate the synthesis of several proteins for rapid adaptation to a different environment. Its protein synthesis has particular characteristics in comparison with higher eukaryotes. For example, the protein-coding genes are organized into polycistronic transcription units; however, in contrast to what occurs in bacterial operons, the polycistronic units must be transcriptionally processed together before translation. In this case, polycistronic RNAs are converted into monocistronic messenger RNAs (mRNAs) through two coupled events: trans-splicing and polyadenylation. During transsplicing, a 39-nt spliced leader (SL) RNA molecule is joined to the 5' terminus of the mature transcript, while a poly(A) tail is polymerized at the 3' terminus. The same polycistronic RNA can contain functionally unrelated genes, which yield very different steady-state mRNA levels and/or which are differentially expressed during the life cycle [see review inAnother trypanosome transcription characteristic is the absence of defined RNA polymerase II (pol II) promoters. There are a few exceptions, however, such as the genes *Address correspondence to these authors at the Instituto Carlos Chagas -ICC, Fiocruz-Paraná, Rua Prof. Algacyr Munhoz Madder 3775, Curitiba, PR. Brazil; Tel: +55-41-33163230; Fax: +55-41-33163267; E-mails: sgoldenb@fiocruz.br, aravi...