Gene expression regulation is a complex process that occurs at multiple steps of the gene expression pathway. While transcription initiation begins the process of gene expression, the post-transcriptional steps of RNA splicing, cleavage-polyadenylation, transport and stability all contribute to the type and final levels of protein that will be produced. In addition, these steps are coupled to each other and to the process of transcription elongation and termination; how this coupling occurs and is regulated is not yet clear. My lab has been studying several different model systems that allow us to address questions of how specific post-transcriptional events are regulated and coupled to each other.
Alternative RNA processing creates a vast diversity of protein products from the surprisingly small number of genes in the human genome; as many as 80% of all genes may be alternatively processed. My lab has been studying the mRNAs encoding the secreted and membrane-bound forms of IgM as a model system to understand developmentally regulated RNA processing. A common precursor RNA is differentially processed at its 3' end to produce these two mRNAs and the pattern of RNA processing varies during B cell development. The regulation of these mRNAs involves a competition between two mutually exclusive RNA processing reactions: cleavage-polyadenylation and RNA splicing. In addition, we have discovered an RNA polymerase II pause site downstream from the secretory-specific poly(A) site that contributes to the balance between the alternative RNA processing reactions. We continue to study the regulation of and connections between the RNA processing and transcription elongation and termination reactions.
In collaboration with the Spear lab, we have been studying the repression of AFP expression that occurs in the mouse liver after birth. By mapping the gene responsible for a natural mouse mutation that leads to incomplete AFP repression, we have identified Zhx2 to be a factor involved in this process. While the promoter of AFP is required for Zhx2-mediated postnatal repression, we have shown that transcription rates do not differ between mice with or without Zhx2. Rather, RNA splicing is inhibited, contributing to the reduction in mRNA. This appears to be a novel regulatory mechanism that couples transcription to a post-transcriptional step of gene expression. We are using tissue culture cell lines as well as transgenic mice to learn more about B cell alternative RNA processing and gene repression during liver development.
Peterson, M.L., C. Ma and B.T. Spear (2011) Zhx2 and ZBTB20: Novel regulators of postnatal alpha-fetoprotein repression and their potential role in gene reactivation during liver cancer. Semin. Cancer Biol. 21:21-27. [Abstract]
Peterson, M.L. (2010) Alternative polyadenylation regulation of immunoglobulin genes. WIRE RNA, Published Online: July 15, 2010. DOI: 10.1002/wrna.36
Gargalovic, P.S., A. Erbilgin, O. Kohannim, J. Pagnon, X. Wang, L. Castellani, R. LeBouf, M.L. Peterson, B.T. Spear, A.J. Lusis (2010) Quantitative trait mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism. Circ Cardiovasc Genet 3: 60-67. [Abstract]
Naidu, S., M.L Peterson and B. Spear (2010) Alpha-fetoprotein related gene (ARG): A new member of the albumin gene family that is no longer functional in primates. Gene, 449:95-102. [Abstract]
Albuquerque, R., T. Hayashi, W. Cho, M.E. Kleinman, A. Takeda, J.Z. Baffi, K. Yamada, H. Kaneko, M.G. Rich, J. Chappell, J. Wilting, H.A. Weich, S. Yamagami, S. Amano, N. Mizuki, J.S. Alexander, M.L. Peterson, R.A. Brekken, M. Hirashima, S. Capoor, T. Usui, B.K. Ambati, J. Ambati (2009) Alternatively spliced VEGF receptor-2 is an essential endogenous inhibitor of lymphatic vessels. Nature Medicine, 15:1023-1030. This article was highlighted in a News and Views in Nature Medicine (2009) 15:993-994. [Abstract]
Perincheri, S., D.K. Peyton, M. Glenn, M.L. Peterson, B.T. Spear (2008) Characterization of the ETnII-α endogenous retroviral element in the BALB/cJ Zxh2Afr1 allele. Mammalian Genome. 19:26-31. [Abstract]
L. Morford, C. Davis, L. Jin, A. Dobierzewska, M.L. Peterson and B.T. Spear (2007) The oncofetal gene Glypican 3 is regulated in postnatal liver by Zinc Fingers and Homeoboxes 2 and in the regenerating liver by Alpha-Fetoprotein Regulator 2. Hepatology, 46:1541-1547. [Abstract]
Peterson, M.L., G.L. Bingham, C. Cowan (2006) Multiple features contribute to the use of the immunoglobulin M secretion-specific poly(A) signal but are not required for developmental regulation. Mol. Cell Biol. 26:6762-6771. [Abstract]
Perincheri, S. , R.W.C. Dingle, M.L. Peterson, and Brett T. Spear (2005) Hereditary persistence of α-fetoprotein and H19 expression in liver of BALB/cJ mice is due to a retrovirus insertion in the Zhx2 gene. PNAS, 102, 396-401 [Abstract]
Bruce, S.R., R.C.W. Dingle and M.L. Peterson (2003) B cell and plasma cell splicing differences: a potential role in regulated immunoglobulin RNA processing. RNA 9, 1264-1273. [Abstract]
Bruce, S.R. and M.L. Peterson. Multiple features contribute to the efficient constitutive splicing of an unusually large exon. Nucleic Acids Res. 29:2292-2302, 2001. [Abstract]
Bruce, S.R., C.S. Kaetzel, and M.L. Peterson. Cryptic intron activation within the large exon of the mouse polymeric immunoglobulin receptor gene: Cryptic splice sites correspond to protein domain boundaries. Nucleic Acids Res. 27:3446-3454, 1999. [Abstract]
Seipelt, R.L., B.T. Spear, E.C. Snow, and M.L. Peterson. A non-Ig transgene and the endogenous Ig µ gene are coordinately regulated by alternative RNA processing during B cell maturation. Mol. Cell. Biol. 18:1042-1048, 1998. [Abstract]
Davidson, J.N. and M.L. Peterson. Origin of genes encoding multienzymatic proteins in eukaryotes. Trends in Genetics, 13:281-285, 1997.
Takagaki, Y., R.L. Seipelt, M.L. Peterson, and J.L. Manley. The polyadenylation factor CstF-64 regulates alternative processing of IgM heavy chain pre-mRNA during B cell differentiation. Cell, 87:941-952, 1996. [Abstract]
Peterson, M.L. Regulated immunoglobulin RNA processing does not require specific cis-acting sequences: Non-Ig genes can be alternatively processed in B cells and plasma cells. Mol. Cell. Biol. 14:7891-7898, 1994. [Abstract]