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Bradley R. Cairns

Professor and Chair of Oncological Sciences and
Adjunct Professor of Biochemistry

Cairns Photo

B.S. Lewis and Clark College

Ph.D. Stanford University

Research

References

brad.cairns@hci.utah.edu

Brad Cairns' Lab Page

Brad Cairns' PubMed Literature Search

Molecular Biology Program

Biological Chemistry Program

Chromatin Transcription, Genomics, Gene Expression

Research

We are interested in epigenetics and chromosome dynamics; how chromatin regulates transcription to influence processes like cell growth, development, and cancer. Questions addressed in our lab include: 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 - how do chromatin changes guide gene expression and embryo development - and how is chromatin misregulated in cancer? We approach these and other biological problems with a variety of techniques including biochemistry, genetics, and genomics. We address these biological problems in yeast, zebrafish, mice and human cells.

Chromatin is remarkably dynamic, as structures formed to silence transcription are remodeled and modified to enable transcription in response to cell signals. The primary unit of chromatin structure is the nucleosome, which wraps genomic DNA like beads on a string. Chromatin transitions are mediated by protein complexes that either reposition nucleosomes, covalently modify nucleosomes, or methylate the DNA – and there is coordination among them. For example, Remodeler complexes use ATP hydrolysis to reposition nucleosomes on the DNA, thereby revealing the underlying sequence to transcriptional regulators. Also, DNA methylation leads to a heritable form of gene silencing, but is regulated by histone modification patterns. We aim to understand these relationships in normal cells, and their misregulation in cancer.

Remodeler mechanism and regulation
We have established that Remodelers use ATP-dependent DNA translocation pump DNA around nucleosomes to expose DNA to transcription factors, and Cedric Clapier & Tim Mulvihill are  testing how the ATPase motor/pump is regulated. Remodelers also bear proteins related to actin, and we are now revealing their role in regulating the DNA pumping motor. Margaret Kasten and Cedric Clapier are working on how Remodelers eject nucleosomes from gene promoters to help promote transcription. Maggie Kasten, Naveen Verma and Alisha Schlichter are investigating how Remodelers work either together, or in opposition, to arrive at the right chromatin structures at gene promoters.

Epigenetics: the regulation of DNA and RNA methylation/demethylation
We have recently examined the dynamic DNA methylome of zebrafish gametes and early embryos, and have discovered that the maternal (egg) genome is reprogrammed to be identical to the paternal (sperm) genome. Mengyao Tan explores the transcription and chromatin factors that set up the nucleosomes and transcriptome of early embryos. Graham Hickey is investigating how chromatin dynamics help regulate development. Vahid Khodammi and Archana Yerra are developing and applying new technologies to understand how RNA methylation is utilized in gene regulation, epigenetics, and on noncoding RNAs.

Germ Cell Chromatinand DNA methylation
We previously provided the first evidence that genes for embryo development are poised by chromatin in the sperm cell. Sue Hammoud, Yixuan Guo, Chongil Yi, Patrick Murphy, Jingtao Guo, and Candice Wike are extending this discovery through 1) the genomics profiling germline stem cells, 2) investigating the mechanisms for poising genes in sperm and eggs for activation or repression in embryos (using zebrafish or mouse models), and 3) exploring connections to transgenerational inheritance and germ cell tumors. Pete Hendrickson, Jessie Dorais, Edward Grow are extending this and related work to human cells.

References

  1. Hendrickson PG, Doráis JA, Grow EJ, Whiddon JL, Lim JW, Wike CL, Weaver BD, Pflueger C, Emery BR, Wilcox AL, Nix DA, Peterson CM, Tapscott SJ, Carrell DT, Cairns BR. (2017) Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat Genet 49(6):925-934
  2. Clapier CR, Kasten MM, Parnell TJ, Viswanathan R, Szerlong H, Sirinakis G, Zhang Y, Cairns BR (2016) Regulation of DNA Translocation Efficiency within the Chromatin Remodeler RSC/Sth1 Potentiates Nucleosome Sliding and Ejection. Molecular Cell 62(3):453-61
  3. Hammoud SS, Low DH, Yi C, Lee CL, Oatley JM, Payne CJ, Carrell DT, Guccione E, Cairns BR (2015) Transcription and imprinting dynamics in developing postnatal male germline stem cells. Genes and Development 29(21):2312-24
  4. Parnell TJ, Schlichter A, Wilson BG, Cairns BR (2015) The chromatin remodelers RSC and ISW1 display functional and chromatin-based promoter antagonism. Elife 4:e06073
  5. Jenkins TG, Aston KI, Pflueger C, Cairns BR, Carrell DT (2014)  Age-associated sperm DNA methylation alterations: possible implications in offspring diseasesusceptibility. PLoS Genet 10(7):e1004458
  6. Hammoud SS, Low DH, Yi C, Carrell DT, Guccione E, Cairns BR (2014) Chromatin and transcription transitions of mammalian adult germline stem cells and spermatogenesis. Cell Stem Cell 15(2):239-53
  7. Potok ME, Nix DA, Parnell TJ, Cairns BR (2013) Reprogramming the maternal zebrafish genome after fertilization to match the paternal methylation pattern. Cell 153(4):759-72
  8. Khoddami V, Cairns BR (2013) Identification of direct targets and modified bases of RNA cytosine methyltransferases. Nature Biotechnology 31(5):458-64
  9. Clapier C and Cairns BR (2012) Regulation of ISWI involves inhibitory modules antagonized by nucleosomal epitopes. Nature 492(7428):280-4
  10. Wu SF, Zhang H, Cairns BR (2011) Genes for embryo development are packaged in blocks of multivalent chromatin in zebrafish sperm. Genome Res 21(4):578-89
  11. Oler AJ, Alla RK, Roberts DN, Wong A, Hollenhorst PC, Chandler KJ, Cassiday PA, Nelson CA, Hagedorn CH, Graves BJ, Cairns BR (2010) Human RNA polymerase III transcriptomes and relationships to Pol II promoter chromatin and enhancer binding factors. Nature Structural & Mol Biol 17(5):620-8
  12. Hammoud S, Nix D, Haiving Z, Purwar J, Carrell D, Cairns BR (2009) Distinctive Human Sperm Chromatin Packages Genes Guiding Embryo Development. Nature 460(7254):473-8
  13. Rai K, Huggins IJ, James SR, Karpf AR, Jones DA, Cairns BR (2008) DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell 135(7):1201-12

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Last Updated: 7/26/17