Bradley R. Cairns
Professor of Oncological Sciences
B.S. Lewis and Clark College
Ph.D. Stanford University
Research
We are interested in chromosome dynamics; how chromatin regulates transcription to influence processes like cell growth and development. What is the state of the genome and chromosomes at the ‘start’ of development - how is the genome packaged and poised in germ cells (sperm and egg) to prepare for embryo development, and how chromatin changes guide embryo development? We approach these and other biological problems with a variety of techniques including biochemistry, genetics, and genomics (microarray and ChIP sequencing). We address these biological problems in yeast, zebrafish, and human cells.
Chromatin is a remarkably dynamic material, as chromosomal structures formed to silence transcription are remodeled and modified to enable transcription in response to cell signals. Chromatin transitions are mediated by a set of protein complexes, which either reposition nucleosomes, covalently modify nucleosomes, or methylate the DNA. DNA methylation leads to an inheritable form of gene silencing. Chromatin remodeling/modifying complexes include:1) histone acetyltransferases (HATs), 2) histone methyltransferase (HMTs), and 3) Remodelers. HAT and HMT complexes covalently mark nucleosomes, whereas Remodelers recognize these marks, and then use the energy of ATP hydrolysis to reposition nucleosomes on the DNA, thereby revealing the underlying sequence to transcriptional regulators. Part of the lab works on how Remodelers recognize nucleosomes via these modifications and how they reposition nucleosomes. We also study how the DNA methylation code is established and altered during development.
Remodeler mechanism and regulation. We have established that Remodelers pump DNA around nucleosomes to expose DNA to transcription factors, and Cedric Clapier is testing how DNA 'waves' travel along the surface of nucleosomes using biochemical and single-molecule approaches. Remodelers also bear proteins related to actin, and Kaede Hinata is now revealing their role in regulating the DNA pumping ‘engine’. Tim Parnell is working on how Remodelers eject nucleosomes from gene promoters to help promote transcription. Alisha Schichter and Maggie Kasten are investigating how Remodelers recognize particular histone modifications to move the right nucleosome. Andrew Oler is focusing on how nutrients and stress regulate transcription and chromatin structure at Pol III genes, which are known RSC targets.
Epigenetics; the regulation of DNA methylation/demethylation. Kunal Rai, Itrat Jafri, and Christian Pflueger are investigating how DNA methylation dynamics help regulate development in zebrafish. We are also establishing a Center for Zebrafish Epigenetics and Chromatin (CZECH)(with David Jones’ lab); which will serve as a resource for genomics and epigenetic work on the zebrafish for the entire community.
Germ Cell Chromatin. Sue Hammoud, Jahnvi Purwar, Shan-Fu Wu, and Magdalena Potok are working on germline chromatin and the mechanisms of poising genes in sperm and eggs for activation or repression in embryos.
References
1. Dutrow N, Nix D, Holt D, Milash B, Dalley B, Westbroek E, Parnell TJ, Cairns BR (2008) Dynamic transcriptome of Schizosaccharomyces pombe shown by RNA-DNA hybrid mapping. Nature Genetics, In Press
2. Szerlong H, Hinata K, Viswanathan R, Erdjument-Bromage H, Tempst P, Cairns BR (2008) The HSA domain binds nuclear actin-related proteins to regulate chromatin-remodeling ATPases. Nature Structural. & Mol Biol. 15(5):469-476
3. Rai K, Chidester S, Svala CV, Manos EJ, James SR, Karpf AR, Jones DA, Cairns BR (2007) Dnmt2 functions in the cytoplasm to promote liver, brain, and retina development in zebrafish. Genes & Dev. 21:(3)261-266
4. Roberts D, Wilson B, Huff J, Stewart A, Cairns BR (2006) Dephosphorylation and genome-wide association of Maf1 with Pol III genes in transcriptional repression. Molecular Cell 22:(5)633-644
5. Zhang H, Roberts D, Cairns BR (2005) Genome-wide dynamics of Htz1, a conserved histone H2A variant that poises repressed genes for activation through histone loss. Cell 123:219-231
6. Saha A, Wittmeyer J, Cairns BR (2005) Chromatin remodeling through directional DNA translocation from an internal nucleosomal site. Nature Structural & Mol. Biol. 12(9):747-55
7. Kasten M, Szerlong H, Erdjument-Bromage H, Tempst P, Werner M, Cairns BR (2004) Tandem bromodomains in the chromatin remodeler RSC recognize acetylated histone H3 Lys14. EMBO J 23:1348-1359
8. Roberts D, Huff J, Stewart A, Cairns BR (2003) The RNA polymerase III transcriptome and basic regulatory strategy revealed by genome-wide occupancy analysis. Proc. Natl. Acad. Sci. 100:14695-14700
9. Szerlong H, Saha A, Cairns BR (2003) The nuclear actin-related proteins Arp7 and Arp9; a dimeric module that cooperates with architectural transcription factors for chromatin remodeling. EMBO J 22:3175-3187
10. Saha A, Wittmeyer J, Cairns BR (2002) Chromatin Remodeling by RSC involves DNA translocation. Genes Dev. 16:2120-2134
