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Bradley R. Cairns

Associate Professor of Oncological Sciences

B.S. Lewis and Clark College

Ph.D. Stanford University

Research

References

brad.cairns@hci.utah.edu

Research

We are interested in chromosome dynamics; how chromatin regulates transcription, recombination and genome stability.  We characterize large protein complexes that remodel chromosomal structure, and use genetic and genomic (DNA microarray and ChIP occupancy microarray) approaches to understand their functions in living cells. 

Chromatin is a remarkably dynamic material, as chromosomal structures formed to silence transcription are remodeled and modified to enable transcription in response to cellular signals.  Chromatin transitions are mediated by a set of multi-protein chromatin remodeling complexes, which affect nucleosomes, the basic repeating unit of chromatin structure.  Transcriptional regulation by nucleosomes is potentiated by the acetylation and methylation of lysine residues on the nucleosome 'tails' according to a complex 'histone code'.  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.  We are interested in how Remodelers recognize nucleosomes via the histone code and how they reposition nucleosomes. We also study how the histone methylation code is established and removed, and how histone variant proteins specialize chromatin.  As chromatin structure is largely conserved in all eukaryotes, most our studies are focused in yeast, where potent genetic and genomic tools can be utilized.   We have also initiated a collaboration with David Jones’ lab to examine how DNA methylation helps regulate development, using zebrafish as a model system.

Remodeler mechanism and regulation. Anjanabha Saha and Jacqueline Wittmeyer have shown that the central function of remodelers is to pump DNA around nucleosomes, and are now testing how DNA 'waves' travel along the surface of nucleosomes during the pumping process.  Remodelers also bear proteins related to actin, and Kaede Hinata and Ramya Viswanathan are now revealing their role in regulating the DNA translocation ‘engine’.  Tim Parnell is working on how Remodelers eject nucleosomes from gene promoters to help promote transcription.

Chromatin regulation through the histone code and DNA methylation. Alisha Schichter is working on understanding how the major histone methyltransferase marks the 5’ ends of active genes and how this affects Remodeler function.   Mat Gordon, Derick Holt, and Anil Panagrahi have purified the complex that removes these methyl marks, and have uncovered all locations in the genome where this marking/unmarking interplay helps regulate transcription (by genomewide microarray localization). Maggie Kasten is investigating how Remodelers read the histone code. Kunal Rai and Itrat Jafri are investigating how DNA methylation and chromatin helps regulate development in zebrafish, a major new effort in the lab.

Histone variants, cell signaling , and cancer connections.  Haiying Zhang uses yeast as a model organism for understanding how fusion proteins in humans cause cancer by improperly depositing histone variants. Andrew Oler is focusing on how nutrients and stress regulate transcription and chromatin structure at Pol III genes, which may help regulate proliferation of cancer cells.  Natalie Dutrow and Dan Richardson examine connections between cellular redox conditions and chromatin structure.

References