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Author Bradley R Cairns

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Cancer-Associated Gain-of-Function Mutations Activate a SWI/SNF-Family Regulatory Hub.

Cedric R Clapier, Naveen Verma, Timothy J Parnell, Bradley R Cairns,

SWI/SNF-family remodelers (BAF/PBAF in mammals) are essential chromatin regulators, and mutations in human BAF/PBAF components are associated with ∼20% of cancers. Cancer-associated missense mutations in human BRG1 (encoding the catalytic ATPase) have been characterized previously as conferring loss-of-function. Here, we show that cancer-associated missense mutations in BRG1, when placed into ... Read more >>

Mol Cell (Molecular cell)
[2020, :]

Cited: 0 times

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Developmentally Programmed Tankyrase Activity Upregulates β-Catenin and Licenses Progression of Embryonic Genome Activation.

Andrés Gambini, Paula Stein, Virginia Savy, Edward J Grow, Brian N Papas, Yingpei Zhang, Anna C Kenan, Elizabeth Padilla-Banks, Bradley R Cairns, Carmen J Williams,

Embryonic genome activation (EGA) is orchestrated by an intrinsic developmental program initiated during oocyte maturation with translation of stored maternal mRNAs. Here, we show that tankyrase, a poly(ADP-ribosyl) polymerase that regulates β-catenin levels, undergoes programmed translation during oocyte maturation and serves an essential role in mouse EGA. Newly translated TNKS ... Read more >>

Dev. Cell (Developmental cell)
[2020, 53(5):545-560.e7]

Cited: 0 times

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The Dynamic Transcriptional Cell Atlas of Testis Development during Human Puberty.

Jingtao Guo, Xichen Nie, Maria Giebler, Hana Mlcochova, Yueqi Wang, Edward J Grow, , Robin Kim, Melissa Tharmalingam, Gabriele Matilionyte, Cecilia Lindskog, Douglas T Carrell, Rod T Mitchell, Anne Goriely, James M Hotaling, Bradley R Cairns,

The human testis undergoes dramatic developmental and structural changes during puberty, including proliferation and maturation of somatic niche cells, and the onset of spermatogenesis. To characterize this understudied process, we profiled and analyzed single-cell transcriptomes of ∼10,000 testicular cells from four boys spanning puberty and compared them to those of ... Read more >>

Cell Stem Cell (Cell stem cell)
[2020, 26(2):262-276.e4]

Cited: 3 times

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Structure of the RSC complex bound to the nucleosome.

Youpi Ye, Hao Wu, Kangjing Chen, Cedric R Clapier, Naveen Verma, Wenhao Zhang, Haiteng Deng, Bradley R Cairns, Ning Gao, Zhucheng Chen,

The RSC complex remodels chromatin structure and regulates gene transcription. We used cryo-electron microscopy to determine the structure of yeast RSC bound to the nucleosome. RSC is delineated into the adenosine triphosphatase motor, the actin-related protein module, and the substrate recruitment module (SRM). RSC binds the nucleosome mainly through the ... Read more >>

Science (Science (New York, N.Y.))
[2019, 366(6467):838-843]

Cited: 6 times

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Genome-wide reconstitution of chromatin transactions reveals that RSC preferentially disrupts H2AZ-containing nucleosomes.

Aylin Cakiroglu, Cedric R Clapier, Andreas H Ehrensberger, Elodie Darbo, Bradley R Cairns, Nicholas M Luscombe, Jesper Q Svejstrup,

Chromatin transactions are typically studied in vivo, or in vitro using artificial chromatin lacking the epigenetic complexity of the natural material. Attempting to bridge the gap between these approaches, we established a system for isolating the yeast genome as a library of mononucleosomes harboring the natural epigenetic signature, suitable for ... Read more >>

Genome Res. (Genome research)
[2019, 29(6):988-998]

Cited: 4 times

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Transcriptome-wide profiling of multiple RNA modifications simultaneously at single-base resolution.

Vahid Khoddami, Archana Yerra, Timothy L Mosbruger, Aaron M Fleming, Cynthia J Burrows, Bradley R Cairns,

The breadth and importance of RNA modifications are growing rapidly as modified ribonucleotides can impact the sequence, structure, function, stability, and fate of RNAs and their interactions with other molecules. Therefore, knowing cellular RNA modifications at single-base resolution could provide important information regarding cell status and fate. A current major ... Read more >>

Proc Natl Acad Sci U S A (Proceedings of the National Academy of Sciences of the United States of America)
[2019, 116(14):6784-6789]

Cited: 11 times

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Isolation and Enrichment of Spermatogonial Stem Cells From Human Testis Tissues.

Jingtao Guo, Bradley R Cairns,

This article describes a protocol for isolating human spermatogonial stem cells (hSSCs) from human testis tissues, which can be utilized for further characterization. Human testis tissues are first subjected to mechanical separation, enzymatic digestion, and physical filtering, yielding a single testicular cell suspension. SSCs or other cell types of interest ... Read more >>

Curr Protoc Stem Cell Biol (Current protocols in stem cell biology)
[2019, 49(1):e77]

Cited: 1 time

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Histone Deacetylase Inhibition Has Targeted Clinical Benefit in ARID1A-Mutated Advanced Urothelial Carcinoma.

Sumati Gupta, Daniel J Albertson, Timothy J Parnell, Andrew Butterfield, Alexis Weston, Lisa M Pappas, Brian Dalley, John M O'Shea, William T Lowrance, Bradley R Cairns, Joshua D Schiffman, Sunil Sharma,

Histone deacetylase (HDAC) inhibition has sporadic clinical efficacy in urothelial carcinoma; the genomic basis for clinical response is not known. In two separate phase I clinical trials testing pharmacokinetic aspects of HDAC inhibitors in advanced solid tumors, we identified one patient with advanced urothelial carcinoma who had a complete response ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2019, 18(1):185-195]

Cited: 1 time

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Placeholder Nucleosomes Underlie Germline-to-Embryo DNA Methylation Reprogramming.

Patrick J Murphy, Shan Fu Wu, Cody R James, Candice L Wike, Bradley R Cairns,

The fate and function of epigenetic marks during the germline-to-embryo transition is a key issue in developmental biology, with relevance to stem cell programming and transgenerational inheritance. In zebrafish, DNA methylation patterns are programmed in transcriptionally quiescent cleavage embryos; paternally inherited patterns are maintained, whereas maternal patterns are reprogrammed to match the ... Read more >>

Cell (Cell)
[2018, 172(5):993-1006.e13]

Cited: 21 times

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Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes.

Cedric R Clapier, Janet Iwasa, Bradley R Cairns, Craig L Peterson,

Cells utilize diverse ATP-dependent nucleosome-remodelling complexes to carry out histone sliding, ejection or the incorporation of histone variants, suggesting that different mechanisms of action are used by the various chromatin-remodelling complex subfamilies. However, all chromatin-remodelling complex subfamilies contain an ATPase-translocase 'motor' that translocates DNA from a common location within the ... Read more >>

Nat. Rev. Mol. Cell Biol. (Nature reviews. Molecular cell biology)
[2017, 18(7):407-422]

Cited: 100 times

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Counteracting H3K4 methylation modulators Set1 and Jhd2 co-regulate chromatin dynamics and gene transcription.

Saravanan Ramakrishnan, Srijana Pokhrel, Sowmiya Palani, Christian Pflueger, Timothy J Parnell, Bradley R Cairns, Srividya Bhaskara, Mahesh B Chandrasekharan,

Histone H3K4 methylation is connected to gene transcription from yeast to humans, but its mechanistic roles in transcription and chromatin dynamics remain poorly understood. We investigated the functions for Set1 and Jhd2, the sole H3K4 methyltransferase and H3K4 demethylase, respectively, in S. cerevisiae. Here, we show that Set1 and Jhd2 ... Read more >>

Nat Commun (Nature communications)
[2016, 7:11949]

Cited: 20 times

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Regulation of DNA Translocation Efficiency within the Chromatin Remodeler RSC/Sth1 Potentiates Nucleosome Sliding and Ejection.

Cedric R Clapier, Margaret M Kasten, Timothy J Parnell, Ramya Viswanathan, Heather Szerlong, George Sirinakis, Yongli Zhang, Bradley R Cairns,

The RSC chromatin remodeler slides and ejects nucleosomes, utilizing a catalytic subunit (Sth1) with DNA translocation activity, which can pump DNA around the nucleosome. A central question is whether and how DNA translocation is regulated to achieve sliding versus ejection. Here, we report the regulation of DNA translocation efficiency by ... Read more >>

Mol Cell (Molecular cell)
[2016, 62(3):453-461]

Cited: 30 times

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Tet proteins enhance the developmental hourglass.

Peter G Hendrickson, Bradley R Cairns,

A new study compares DNA methylation profiles in developing zebrafish, Xenopus tropicalis and mice and suggests roles for Tet proteins in demethylating conserved gene enhancers during the phylotypic period of early development. These findings provide an epigenetic underpinning for the 'hourglass' model. ... Read more >>

Nat. Genet. (Nature genetics)
[2016, 48(4):345-347]

Cited: 1 time

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Interaction of the Jhd2 Histone H3 Lys-4 Demethylase with Chromatin Is Controlled by Histone H2A Surfaces and Restricted by H2B Ubiquitination.

Fu Huang, Saravanan Ramakrishnan, Srijana Pokhrel, Christian Pflueger, Timothy J Parnell, Margaret M Kasten, Simon L Currie, Niraja Bhachech, Masami Horikoshi, Barbara J Graves, Bradley R Cairns, Srividya Bhaskara, Mahesh B Chandrasekharan,

Histone H3 lysine 4 (H3K4) methylation is a dynamic modification. In budding yeast, H3K4 methylation is catalyzed by the Set1-COMPASS methyltransferase complex and is removed by Jhd2, a JMJC domain family demethylase. The catalytic JmjC and JmjN domains of Jhd2 have the ability to remove all three degrees (mono-, di-, ... Read more >>

J Biol Chem (The Journal of biological chemistry)
[2015, 290(48):28760-28777]

Cited: 5 times

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Aberrant sperm DNA methylation predicts male fertility status and embryo quality.

Kenneth I Aston, Philip J Uren, Timothy G Jenkins, Alan Horsager, Bradley R Cairns, Andrew D Smith, Douglas T Carrell,

To evaluate whether male fertility status and/or embryo quality during in vitro fertilization (IVF) therapy can be predicted based on genomewide sperm deoxyribonucleic acid (DNA) methylation patterns.Retrospective cohort study.University-based fertility center.Participants were 127 men undergoing IVF treatment (where any major female factor cause of infertility had been ruled out), and ... Read more >>

Fertil. Steril. (Fertility and sterility)
[2015, 104(6):1388-97.e1-5]

Cited: 43 times

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Experimental Approaches for Target Profiling of RNA Cytosine Methyltransferases.

Vahid Khoddami, Archana Yerra, Bradley R Cairns,

RNA cytosine methyltransferases (m(5)C-RMTs) constitute an important class of RNA-modifying enzymes, methylating specific cytosines within particular RNA targets in both coding and noncoding RNAs. Almost all organisms express at least one m(5)C-RMT, and vertebrates often express different types or variants of m(5)C-RMTs in different cell types. Deletion or mutation of ... Read more >>

Meth. Enzymol. (Methods in enzymology)
[2015, 560:273-296]

Cited: 3 times

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Transcription and imprinting dynamics in developing postnatal male germline stem cells.

Saher Sue Hammoud, Diana H P Low, Chongil Yi, Chee Leng Lee, Jon M Oatley, Christopher J Payne, Douglas T Carrell, Ernesto Guccione, Bradley R Cairns,

Postnatal spermatogonial stem cells (SSCs) progress through proliferative and developmental stages to populate the testicular niche prior to productive spermatogenesis. To better understand, we conducted extensive genomic profiling at multiple postnatal stages on subpopulations enriched for particular markers (THY1, KIT, OCT4, ID4, or GFRa1). Overall, our profiles suggest three broad ... Read more >>

Genes Dev. (Genes & development)
[2015, 29(21):2312-2324]

Cited: 22 times

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The chromatin remodelers RSC and ISW1 display functional and chromatin-based promoter antagonism.

Timothy J Parnell, Alisha Schlichter, Boris G Wilson, Bradley R Cairns,

ISWI family chromatin remodelers typically organize nucleosome arrays, while SWI/SNF family remodelers (RSC) typically disorganize and eject nucleosomes, implying an antagonism that is largely unexplored in vivo. Here, we describe two independent genetic screens for rsc suppressors that yielded mutations in the promoter-focused ISW1a complex or mutations in the 'basic ... Read more >>

Elife (eLife)
[2015, 4:e06073]

Cited: 26 times

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SINE transcription by RNA polymerase III is suppressed by histone methylation but not by DNA methylation.

Dhaval Varshney, Jana Vavrova-Anderson, Andrew J Oler, Victoria H Cowling, Bradley R Cairns, Robert J White,

Short interspersed nuclear elements (SINEs), such as Alu, spread by retrotransposition, which requires their transcripts to be copied into DNA and then inserted into new chromosomal sites. This can lead to genetic damage through insertional mutagenesis and chromosomal rearrangements between non-allelic SINEs at distinct loci. SINE DNA is heavily methylated ... Read more >>

Nat Commun (Nature communications)
[2015, 6:6569]

Cited: 35 times

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HDAC1,2 inhibition impairs EZH2- and BBAP-mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma.

Danielle P Johnson, Gabriella S Spitz, Shweta Tharkar, Steven N Quayle, Jeffrey R Shearstone, Simon Jones, Maria E McDowell, Hannah Wellman, Jessica K Tyler, Bradley R Cairns, Mahesh B Chandrasekharan, Srividya Bhaskara,

Gain-of-function mutations in the catalytic site of EZH2 (Enhancer of Zeste Homologue 2), is observed in about 22% of diffuse large B-cell lymphoma (DLBCL) cases. Here we show that selective inhibition of histone deacetylase 1,2 (HDAC1,2) activity using a small molecule inhibitor causes cytotoxic or cytostatic effects in EZH2 gain-of-function ... Read more >>

Oncotarget (Oncotarget)
[2015, 6(7):4863-4887]

Cited: 17 times

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Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility.

Timothy G Jenkins, Kenneth I Aston, Christian Pflueger, Bradley R Cairns, Douglas T Carrell,

Recent evidence demonstrates a role for paternal aging on offspring disease susceptibility. It is well established that various neuropsychiatric disorders (schizophrenia, autism, etc.), trinucleotide expansion associated diseases (myotonic dystrophy, Huntington's, etc.) and even some forms of cancer have increased incidence in the offspring of older fathers. Despite strong epidemiological evidence ... Read more >>

PLoS Genet. (PLoS genetics)
[2014, 10(7):e1004458]

Cited: 84 times

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Chromatin and transcription transitions of mammalian adult germline stem cells and spermatogenesis.

Saher Sue Hammoud, Diana H P Low, Chongil Yi, Douglas T Carrell, Ernesto Guccione, Bradley R Cairns,

Adult germline stem cells (AGSCs) self-renew (Thy1(+) enriched) or commit to gametogenesis (Kit(+) enriched). To better understand how chromatin regulates AGSC biology and gametogenesis, we derived stage-specific high-resolution profiles of DNA methylation, 5hmC, histone modifications/variants, and RNA-seq in AGSCs and during spermatogenesis. First, we define striking signaling and transcriptional differences ... Read more >>

Cell Stem Cell (Cell stem cell)
[2014, 15(2):239-253]

Cited: 114 times

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RNA polymerase III transcriptomes in human embryonic stem cells and induced pluripotent stem cells, and relationships with pluripotency transcription factors.

Ravi K Alla, Bradley R Cairns,

Recent genomic approaches have revealed that the repertoire of RNA Pol III-transcribed genes varies in different human cell types, and that this variation is likely determined by a combination of the chromatin landscape, cell-specific DNA-binding transcription factors, and collaboration with RNA Pol II. Although much is known about this regulation ... Read more >>

PLoS One (PloS one)
[2014, 9(1):e85648]

Cited: 17 times

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Transcriptome-wide target profiling of RNA cytosine methyltransferases using the mechanism-based enrichment procedure Aza-IP.

Vahid Khoddami, Bradley R Cairns,

Cytosine methylation within RNA is common, but its full scope and functions are poorly understood, as the RNA targets of most mammalian cytosine RNA methyltransferases (m(5)C-RMTs) remain uncharacterized. To enable their characterization, we developed a mechanism-based method for transcriptome-wide m(5)C-RMT target profiling. All characterized mammalian m(5)C-RMTs form a reversible covalent ... Read more >>

Nat Protoc (Nature protocols)
[2014, 9(2):337-361]

Cited: 11 times

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Reintroducing domesticated wild mice to sociality induces adaptive transgenerational effects on MUP expression.

Adam C Nelson, Joseph W Cauceglia, Seth D Merkley, Neil A Youngson, Andrew J Oler, Randy J Nelson, Bradley R Cairns, Emma Whitelaw, Wayne K Potts,

When brought into captivity, wild animals can adapt to domestication within 10 generations. Such adaptations may decrease fitness in natural conditions. Many selective pressures are disrupted in captivity, including social behavioral networks. Although lack of sociality in captivity appears to mediate domestication, the underlying mechanisms are not well understood. Additionally, ... Read more >>

Proc. Natl. Acad. Sci. U.S.A. (Proceedings of the National Academy of Sciences of the United States of America)
[2013, 110(49):19848-19853]

Cited: 16 times

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