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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 embryonic 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 and the enzyme complexes that conduct these processes in normal cells, and their misregulation in cancer.

Remodeler Mechanism and Regulation
Our lab has made fundamental contributions to Remodeler mechanisms and regulation.  We established that Remodelers use ATP-dependent DNA translocation pump DNA around nucleosomes to conduct nucleosome sliding and ejection to expose DNA to transcription factors, and have revealed many regulatory domains and proteins.  Now, Cedric Clapier, Tim Mulvihill, Naveen Verma and Mary Nelson are testing how the ATPase motor/pump is regulated to conduct nucleosome sliding and ejection, and are reconstituting multi-protein Remodeler complexes (and oncogenic variants) from bacterial and human cell overexpression systems. Margaret Kasten and Alisha Schlichter are investigating how Remodelers are specialized to work together to arrive at the right chromatin structures at highly active gene promoters.

Defining ‘On’ and ‘Off’ Genes in the Early Vertebrate Embryo
We have recently examined the dynamic chromatin of zebrafish gametes and early embryos, and have discovered that the chromatin of the maternal (egg) genome is reprogrammed to be identical to the paternal (sperm) genome during the first cell cycles of the zebrafish embryo. Graham Hickey, Yixuan Guo and Candice Wike are exploring the transcription and chromatin factors and structures sculpt the chromatin landscape of early embryos to define which genes are on, and which are off, at the onset of zygotic transcription. We have recently uncovered an ordered pathway of transcription factors, histone variants, and histone modification complexes that ‘poise’ developmental genes for future activation, or alternatively activate housekeeping genes - and how they work to reprogram the maternal genome.  Our work in zebrafish embryos complements our work on mammalian embryos, below.

Chromatin Programming in Germ Cells and Embryos to create ‘Totipotency’
We previously provided the first evidence that genes for embryo development are poised by chromatin in the sperm cell. We have extended this to understand the chromatin and transcription pathways that are present in spermatogonial stem cells (SSCs), to better understand ‘totipotency’ – the ability to become any cell type.  To better understand totipotency, the lab explores both the mammalian germline and early embryos.  To extend our work in the germline, Jingtao Guo, Chongil Yi and Xichen Nie have established a transcriptional and chromatin ‘cell atlas’ of the human testis using single-cell approaches (which we will soon extend to examine puberty) to understand how the germline stem cells regulate their chromatin and transcription during spermatogenesis. Regarding our work in mammalian embryos, work by Pete Hendrickson discovered a major driver of embryo transcription and chromatin structure in mammals, termed DUX.  Here, Edward Grow, Christy Smith, Brad Weaver and Sean Shadle and are greatly extending this work to understand how DUX factors are regulated, and how they help enable all developmental fates.

References

  1. Murphy PJ, Wu SF, James CR, Wike CL, Cairns BR (2018) Placeholder Nucleosomes Underlie Germline-to-Embryo DNA Methylation Reprogramming. Cell 172(5):993-1006

  2. Guo J, Grow EJ, Yi C, Mlcochova H, Maher GJ, Lindskog C, Murphy PJ, Wike CL, Carrell DT, Goriely A, Hotaling JM, Cairns BR. (2017) Chromatin and Single-Cell RNA-Seq Profiling Reveal Dynamic Signaling and Metabolic Transitions during Human Spermatogonial Stem Cell Development. Cell Stem Cell 21(4):533-546

  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. Khoddami V, Cairns BR (2013) Identification of direct targets and modified bases of RNA cytosine methyltransferases. Nature Biotechnology 31(5):458-64
  11. Clapier C and Cairns BR (2012) Regulation of ISWI involves inhibitory modules antagonized by nucleosomal epitopes. Nature 492(7428):280-4
  12. 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
  13. 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
  14. 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
  15. 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: 7/16/19