Brett Spear, Ph.D.

Research Description: 

My research interests are in the area of mammalian gene regulation; in particular, we are interested in transcriptional regulation in the liver during development and disease.  Liver-specific regulation of the mouse alpha-fetoprotein (AFP) gene is being investigated using a variety of biochemical and molecular genetic strategies in tissue culture cells and transgenic mice. In vitro studies allow us to characterize the interplay between transcription factors and AFP regulatory elements such as the AFP promoter and enhancers. AFP constructs are analyzed in liver cell lines to further explore the consequences of these interactions. Finally, to fully understand aspects of AFP regulation, we introduce AFP DNA constructs into the mouse germline to produce transgenic animals. Using the tools and resources of the human genome project, we recently cloned Zhx2 as a regulator of AFP expression.  We are currently investigating the role of Zhx2 in the control of AFP as well as other hepatic genes.  Interestingly, we have found that Zhx2 regulates liver genes that control serum lipid levels and can influence cardiovascular disease.  We have generated a conditional null allele of Zhx2 and are using these mice to study the role of this factor in liver development, liver disease (including cancer) and cardiovascular disease.  

We are also interested in how transcription factors are involved in the response to agents that cause liver damage and/or liver cancer. In particular, we are studying the response to peroxisome proliferators, phenobarbital, and PCBs. We are interested in the link between these chemicals, nutritional status, oxidative stress, transcription factors, epigenetic events, and liver cancer.  These studies emphasize the use of transgenic and gene knock-out mice.

Selected Publications: 

Peterson, M., C. Ma, and B.T. Spear.  2011. Zhx2 and Zbtb20, novel regulators of postnatal AFP expression and their potential role in gene reactivation during liver cancer.  Sem Cancer Biol., 21:21-27. PDF

Liu, H., H. Ren, and B.T. Spear. 2011. The mouse alpha-albumin (Afamin) promoter is differentially regulated by HNF1a and HNF1b. DNA & Cell Biology,  30:137-147.

Glauert, H.P., K. Calfee-Mason, D.N. Stemm, J.C. Tharappel and B.T. Spear.  2010.  Dietary antioxidants in the prevention of hepatocarcinogenesis.  Molec. Nutr. Food Res  54:875-896

Gargalovic, P.S., A. Erbilgin, O. Kohanim, J. Pagnon, X. Wang, L. Castellani, R. LeBeouf, M.L,Peterson, B.T. Spear and A.J. Lusis.  2010.  Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism.  Cir. Cardiovasc. Genetics.  3:60-67. PDF

Naidu, S., M.L. Peterson and B.T. 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. PDF

Jin, L., L. Long, M.A. Green and B.T. Spear.  2009.  The alpha-fetoprotein enhancer region facilitates RNA polymerase loading and activates the albumin and alpha-fetoprotein promoters during liver development.  Dev. Biol., 336:294-300 PDF

Green, M.A., S. Bass and B. Spear.  2009.  A device for the simple and rapid transcervical transfer of mouse embryos eliminates the need for surgery and potential post-operative complications. Biotechniques, 47: 919-924 PDF

Glauert, H.P., J.C. Tharappel, S. Banerjee, L.S. Chan, I. Kania-Korwel, H.-J. Lehmler, E.Y. Lee, L.W.  Robertson, and B.T. Spear.  (2008)  Inhibition of the promotion of hepatocarcinogenesis by 2,2’,4,4’,5,5’-Hexachlorobiphenyl (PCB-153) by the deletion of the p50 Subunit of NF-kB in mice.  Toxicol Appl Pharmacol. 232:302-308. PDF

Perincheri, S., D.K. Peyton, M. Glenn, M.L. Peterson, and B.T. Spear.  (2008)  Characterization of the ETnII-a  endogenous retroviral element in the BALB/cJ Zhx2Afr1 allele.  Mammalian Genome. 19: 26-31. PDF

Morford, L.A., C. Davis, L. Jin, A. Dobierzewska, M.L. Peterson, and B.T. Spear.  (2007)  The oncofetal gene Glypican 3 is regulated in the postnatal liver by Zinc  Fingers and Homeoboxes Protein 2 and in the regenerating liver by Alpha-fetoprotein regulator  2.  Hepatology, 46(5):1541-1547. PDF

Spear, B.T., L. Jin, S. Ramaswamy, and A. Dobierzewska.  (2006)  Transcriptional control in the mammalian liver:  Liver development, perinatal repression, and zonal gene regulation.  Cellular and Molecular Life Sciences 63:2922-2938. PDF

Perincheri, S., R.W.C. Dingle, M.L. Peterson and B.T. Spear.  (2005)  Hereditary persistence of alpha-fetoprotein and H19 expression in BALB/cJ mouse liver is caused by a hypomorphic mutation in the zinc-fingers and homeoboxes gene, Zhx2.  Proc.Natl.Acad.Sci., USA, 102:396-401. PDF