Birchler Lab

The Birchler Lab originally began at Harvard University in Cambridge, MA. In 1993, the Birchler Lab moved to its current location in 117 Tucker Hall on the campus of the University of Missouri–Columbia. The lab is run by Dr. James A. Birchler.

Research Overview

Their longest standing research area has been how changes in chromosomal dosage affect gene expression and the organism. The results indicate that most regulatory processes in multicellular eukaryotes have evolved to be expressed at a level and to operate in such a manner that they are rate limiting on phenotypic characteristics. This property of regulatory mechanisms has implications for a number of genetic phenomena as described below.

Both positive and negative dosage effects operate, although the latter are in the majority. One dose of a chromosome arm often increases target gene expression throughout the genome approximately two-fold relative to the normal diploid. The corresponding three doses can reduce gene expression to a lower limit of two thirds. If such modulation is produced by a chromosomal arm and it has an effect on a target gene varied on the same segment, the change in structural gene dosage is cancelled by this “inverse dosage effect” and dosage compensation results.

They are interested in how dosage dependent regulatory genes control the process of X chromosomal dosage compensation in Drosophila. Their recent work suggests that as the heteromorphic sex chromosomes have evolved, a redistribution of a histone acetylase has occurred to modify how the regulatory dosage effects of the single X in males alter target gene expression. The acetylase is sequestered from the autosomes to prevent the increased expression expected from the prevalence of negatively acting dosage regulators. When the complex is genetically destroyed, the acetylase returns to the autosomes and gene expression increases.

They have also found that hybrid vigor (heterosis) is apparently controlled by dosage dependent regulatory genes. Triploid inbreds and hybrids were produced and compared to diploid inbreds and hybrids. In the triploid situation, there are two types of hybrids (AAB and ABB). When measures of hybrid vigor were applied, the two types differed, indicating an influence of allelic dosage. Preliminary tests of gene expression of randomly selected genes show that hybrids exhibit increased or decreased gene expression per cell. The results have led us to the model that heterosis is a reflection of the fact that most regulatory processes are dosage dependent and that the vast majority of these genes act negatively. If they work less efficiently in hybrids, most target gene expression would be increased.

The lab also studies dispersed transgene silencing (cosuppression) in Drosophila. One type involves a transcriptional process in which the silenced transgenes are associated with the Polycomb group of repressive chromatin proteins. The second involves a posttranscriptional RNA turnover mechanism that possesses the molecular hallmarks characteristic of RNA interference. These mechanisms most likely exist as a genomic defense against transposon mobility and as a cellular shield against viruses. Recent studies in our lab have demonstrated that RNAi machinery is needed for Polycomb dependent transcriptional silencing as well as for proper heterochromatin formation.

Several years ago the laboratory cloned a repeat associated with the maize supernumerary chromosome centromere. Critical regions of this centromere have been defined that permit high fidelity of meiotic transmission. Current studies are involved with understanding the structure of the centromere repeats and their evolution. Also, we are in the process of using these fragments to attempt construction of maize artificial chromosomes, for which we are developing a wide variety of vectors and approaches. As an alternative, we have generated numerous minichromosomes containing little more than the centromere of the supernumerary chromosome, which could be purified and used in constructing yet a different type of vector. The eventual development of artificial chromosome technology will permit the directed study of the components needed for chromosomal behavior as well as many industrial applications. The ability to introduce complete biochemical pathways might confer new properties to the target plant or allow plants to be used as biological factories for the economical production of a desired end-product.

Lab Members - Current and Past
* James Birchler - Principal investigator

*Don Auger - Postdoctoral researcher
*Matthew Bauer - Graduate Student
*Utpal Bhadra - Postdoctoral researcher
*Manika Pal Bhadra - Postdoctoral researcher
*Jenny Cooper - Graduate Student
*Doug Davis
*Tatiana Danilova - Postdoctoral researcher
*Christopher Della Vedova - Graduate Student
*Mei Guo - Postdoctoral researcher
*Akio Kato - Postdoctoral researcher
*Etienne Kaszas
*Harsh Kavi - Graduate Student
*Jonathan Lamb - Graduate Student
*Rick Masonbrink - Graduate Student
*Peggy Northup - Lab Technician
*Tara Phelps-Dur - Graduate Student
*Brent Page - Graduate Student
*James Theuri - Postdoctoral researcher

Publications

For a list of current published research articles, please click on [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?dbpubmed&cmdSearch&itoolpubmed_AbstractPlus&term%22Birchler+JA%22%5BAuthor%5D here]

*Leonard Rabinow and James A. Birchler, 1989. A dosage sensitive modifier of retrotransposon induced alleles of the white locus of Drosophila. The EMBO Journal 8: 879-890.

*James A. Birchler, John C. Hiebert and Leonard J. Rabinow, 1989. Interaction of the mottler of white with transposable element alleles at the white locus in Drosophila melanogaster. Genes and Development 3: 73-84.

*Mei Guo and James A. Birchler, 1994. Trans-acting dosage effects on the expression of model gene systems in maize aneuploids. Science 266: 1999-2002.

*Mei Guo, Doug Davis and James A. Birchler, 1996. Dosage effects on gene expression in a maize ploidy series. Genetics 142: 1349-1355.

*James A. Birchler, 1996. X chromosome dosage compensation in Drosophila. Science 272: 1190.

*Etienne Kaszas and James A. Birchler, 1996. Misdivision analysis of centromere structure in maize. EMBO Journal 15: 5246-5255.

*Manika Pal-Bhadra, Utpal Bhadra and James A. Birchler, 1997. Cosuppression in Drosophila: gene silencing of Alcohol dehydrogenase by white-Adh transgenes is Polycomb dependent. Cell 90: 479-490.

*Manika Pal Bhadra, Utpal Bhadra and James A. Birchler, 1999. Cosuppression of non-homologous transgenes in Drosophila involves mutually related endogenous sequences. Cell 99: 35-46.

*Brent T. Page, Michael K. Wanous and James A. Birchler, 2001. Characterization of a maize chromosome 4 centromeric sequence: evidence for an evolutionary relationship with the B chromosome centromere. Genetics 159: 291-302.

*Manika Pal Bhadra, Utpal Bhadra and James A. Birchler, 2002. RNAi related mechanisms affect both transcriptional and post-transcriptional transgene silencing in Drosophila. Molecular Cell 9: 315-327.

*Cathy X. Zhong, Joshua B. Marshall, Christopher Topp, Rebecca Mroczek, Akio Kato, Kiyotaka Nagaki, James A. Birchler, Jiming Jiang and R. Kelly Dawe, 2002. Centromeric retroelements and satellites interact with maize kinetochore protein CENH3. The Plant Cell 14: 2825-2836.

*Manika Pal Bhadra, Boris A Leibovitch, Sumit G. Gandhi, Madhusudana Rao, Utpal Bhadra, James A. Birchler and Sarah C. R. Elgin, 2004. Heterochromatic silencing and HP1 localization in Drosophila are dependent on the RNAi machinery. Science 303: 669-672.

*Jin W, Lamb JC, Vega JM, Dawe RK, Birchler JA, Jiang J., 2005. Molecular and functional dissection of the maize B chromosome centromere. Plant Cell. May;17(5):1412-23.

*Han F, Lamb JC, Birchler JA., 2006 High frequency of centromere inactivation resulting in stable dicentric chromosomes of maize. Proc Natl Acad Sci U S A. 2006. Feb 28;103(9):3238-43.

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