bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B01: Biological consequences of histone mutations in the mammalian brain
Authors: Larson Jon D. , Kasper Lawryn H. , Russell Helen R. , Qu Chunxu , Zhu Xiaoyan , McKinnon Peter J. , Baker Suzanne J. 
Published: May 2016

Abstract
Pediatric high-grade gliomas (HGGs) are devastating diseases with poor prognosis. The two-year survival for pediatric HGG ranges from 30%, for tumors arising in the cerebral cortex, to less than 10% for diffuse intrinsic pontine gliomas (DIPGs), which arise in the brainstem. Recurrent somatic mutations in histone H3 found in pediatric HGGs are rare in adult HGGs and may represent genetic drivers of disease. Mutually exclusive somatic heterozygous H3F3A or HIST1H3B mutations encoding a K27M variant of histone H3.3 or H3.1, respectively, are found in nearly 80 percent of DIPGs and 22 percent of non-brainstem HGG, where they occur predominantly in thalamic and other midline tumors. Strikingly, heterozygous H3F3A mutations encoding histone H3.3 G34R or G34V occur in approximately 14 percent of non-brainstem HGG, and are associated predominantly with cortical tumors arising in older children through young adulthood, suggesting a distinct developmental origin compared to the majority of tumors harboring K27M mutations. DNA methylation signatures and gene expression patterns distinguish G34R/V and K27M tumors, but the oncogenic mechanisms and brain region selectivity of these mutations are still uncertain. To study these mutations in the developing mammalian brain, we generated conditionally activated, epitope tagged H3f3a knock-in mice to express K27M, G34R or non-mutated H3.3 proteins. When activated in neural and glial precursor cells, extensive H3f3a expression was observed throughout the embryonic brain, and H3.3-K27M induced loss of H3K27me3, consistent with observations in K27M mutant DIPG tumor samples. Moreover, neural stem cells expressing H3.3-K27M demonstrated an in vitro growth advantage compared to H3.3-G34R or H3.3-WT expressing neural stem cells. We will present an analysis of the epigenetic landscape and gene expression signatures associated with the histone H3 K27M and G34R mutations in different brain regions as well as phenotypic analysis of the mutant mice.
Citation Format: Jon D. Larson, Lawryn H. Kasper, Helen R. Russell, Chunxu Qu, Xiaoyan Zhu, Peter J. McKinnon, Suzanne J. Baker. Biological consequences of histone mutations in the mammalian brain. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B01.
Abstract B02: The role of chromatin remodeler protein ARID1a in ovarian clear cell carcinoma
Authors: Lakshminarasimhan Ranjani , Andreu-Vieyra Claudia , Lawrenson Kate , Gayther Simon A. , Jones Peter A. , Liang Gangning 
Published: May 2016

Abstract
Ovarian cancer is the fifth leading cause of cancer death among women in the United States and ovarian clear cell carcinoma (OCCC) is an aggressive subtype of epithelial ovarian cancer. Recent whole genome and whole exome sequencing studies have revealed that the chromatin remodeler protein AT-Rich Interactive Domain 1a (ARID1a) is frequently mutated in OCCC. ARID1a loss is also often observed in endometriosis which is strongly associated with OCCC. Consequently, we hypothesize that loss of ARID1a is an early step in transformation of endometriosis into OCCC. Here, we show that knocking down ARID1a in an immortalized endometriosis line, promotes greater invasion of basement membrane in vitro, and higher efficiency of anchorage-independent growth. Using two independent genome wide approaches to assay chromatin accessibility and DNA methylation, we demonstrate that the loss of ARID1a does not significantly alter global chromatin accessibility and DNA methylation with the exception of the genomic regions containing late replicating domains. Our findings do however indicate that the loss of ARID1a contributes to altered distribution of H3K27me3 and H3K27ac marks. Specifically we find an increased deposit of the polycomb repressive mark in the knock-down line outside of promoters. Interestingly, we also find the knock-down line has a higher level of the active mark H3K27ac at the promoters and a lower level at the enhancers relative to the scrambled control. Moreover, many of the genes differentially expressed upon ARID1a knock-down are consistent with the changes of H3K27ac at the respective gene promoter. We therefore conclude that loss of ARID1a expression contributes to cellular transformation through deregulation of gene expression primarily through alteration of histone marks.
Citation Format: Ranjani Lakshminarasimhan, Claudia Andreu-Vieyra, Kate Lawrenson, Simon A. Gayther, Peter A. Jones, Gangning Liang. The role of chromatin remodeler protein ARID1a in ovarian clear cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B02.
Abstract B03: Identification of epigenetic regulated genes through simultaneous analysis of DNA methylation and chromatin structure in uncultured tumors
Authors: Becket Elinne , Chopra Sameer , Duymich Christopher , Justin Lin J. , You Jueng Soo , Pandiyan Kurinji , Nichols Peter W. , Siegmund Kimberly D. , Jones Peter A. , Liang Gangning 
Published: May 2016

Abstract
The contribution of promoter DNA methylation to the alteration of caner related gene expression has been well studied, however, these genes can also potentially be altered by chromatin accessibility without involvement of DNA methylation and can be epigenetically inherited. In this study, we used an assay developed in our laboratory (AcceSssIble) that can simultaneously interrogate DNA methylation and chromatin accessibility allowing us to investigate the epigenetic changes in uncultured clear cell renal cell carcinoma (ccRCC) tumors and normal tissue to uncover genes that contribute to ccRCC tumorigenesis. AcceSssIble is both cost-effective and easily analyzed using simple and straightforward computational analysis. Our study revealed significant changes to the epigenome of ccRCC, especially identifying epigenetically up- (160) or down-regulated genes (180), which are dependent on accessibility changes with (30%) or without (70%) DNA methylation involvement, and which were validated by a cross-correlation of the identified genes with RNA-seq and DNA methylation data from larger cohorts of ccRCC samples from The Cancer Genome Atlas (TCGA). In addition, our findings also revealed these sets of genes not found to be commonly mutated in ccRCC and undergo epigenetic changes at higher frequencies than common ccRCC mutations. In addition, pathway analysis suggests that genetic and epigenetic alterations are independent events, and one such example includes a set of changes in HIF1α signaling pathway genes that are independent of the Von Hippel-Lindau (VHL) status. This suggests a novel epigenetic basis for HIF1αs role during tumorigenesis that may be a common occurrence in ccRCC. Thus, the AcceSssIble analysis on ccRCC samples revealed novel candidates for epigenetic driver genes which were previously undetectable by widely used methylation studies. Overall, this study provides a novel approach that can help identify new epigenetic therapeutic targets and treatment strategies complementing current approaches based primarily on the genetic makeup of primary tumors.
Citation Format: Elinne Becket, Sameer Chopra, Christopher Duymich, Lin J. Justin, Jueng Soo You, Kurinji Pandiyan, Peter W. Nichols, Kimberly D. Siegmund, Peter A. Jones, Gangning Liang. Identification of epigenetic regulated genes through simultaneous analysis of DNA methylation and chromatin structure in uncultured tumors. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B03.
Abstract B21: Integrated genomic and functional analyses of histone demethylases identify oncogenic KDM2A isoform in breast cancer
Authors: Yang Zeng-Quan 
Published: May 2016

Abstract
Histone lysine demethylases (KDMs) comprise a large class of enzymes that catalyze site-specific demethylation of lysine residues on histones and other proteins. They play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of KDMs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of 24 KDMs in breast cancer and identified associations among recurrent copy number alterations, gene expression, breast cancer subtypes, and clinical outcome. Two KDMs, KDM2A and KDM5B, had the highest frequency of genetic amplification and overexpression. Furthermore, among the 24 KDM genes, KDM2A had the highest correlation between copy number and mRNA expression, and high mRNA levels of KDM2A were significantly associated with shorter survival of breast cancer patients. KDM2A has two isoforms: the long isoform is comprised of a JmjC domain, CXXC-zinc finger, PHD zinc finger, F-box, and the AMN1 protein domain; whereas the short isoform of KDM2A lacks the N-terminal JmjC domain but contains all other motifs. Detailed characterization of KDM2A in breast cancer revealed that the short isoform of KDM2A is more abundant than the long isoform at DNA, mRNA, and protein levels in a subset of breast cancers. Furthermore, our data indicate that the short isoform of KDM2A has oncogenic potential and functions as an oncogenic isoform in a subset of breast cancers. Taken together, our findings suggest that amplification and overexpression of the KDM2A short isoform is critical in breast cancer progression.
Citation Format: Zeng-Quan Yang. Integrated genomic and functional analyses of histone demethylases identify oncogenic KDM2A isoform in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B21.
Abstract B30: Targeting EZH2 methyltransferase activity: A novel therapeutic approach to ARID1A-deficient cancer
Authors: Bitler Benjamin , Garipov Azat , Shih Ie Ming , Zhang Rugang 
Published: May 2016

Abstract
Loss of function mutation of the epigenetic modulator ARID1A, a component of SWI/SNF chromatin remodeling complex, occurs in a number of cancers most notably ovarian. ARID1A is mutated in up to 60% and 30% of clear cell and endometrioid ovarian cancers, respectively. However, there currently is no effective therapy that targets ARID1A-deficient human cancers. Here we show ARID1A-deficient ovarian cancer cells are selectively sensitive to inhibition of EZH2's methyltransferase activity. EZH2 is the catalytic subunit of the polycomb repressor complex 2, which represses gene expression by generating tri-methylation epigenetic mark on lysine 27 of histone H3 (H3K27Me3). Utilizing a library of small molecules against epigenetic targets, we identified an EZH2 small molecule inhibitor that selectively inhibited the growth of ARID1A-deficient ovarian cancer cells, while exhibiting no effects in ARID1A wild-type cells. Genome-wide gene expression profile revealed that there is significant overlap of genes altered by ARID1A restoration and EZH2 methyltransferase inhibition. Specifically, the tumor suppressor and inhibitor of PI3K/AKT signaling, PIK3IP1, is regulated by both ARID1A and EZH2. Chromatin immunoprecipitation assays confirmed the occupancy of ARID1A and EZH2 at the PIK3IP1 promoter. In an intraperitoneal (IP) xenograft mouse model, EZH2 inhibitor GSK126 treatment resulted in a significant decrease in the number of IP tumor nodules. Moreover, in an independent orthotopic intra-bursal xenograft model using ARID1A wildtype and deficient cells, the EZH2 inhibitor GSK126 only suppressed the growth of ARID1A-deficient tumors. Notably, the observed effects correlated with a decrease in expression of H3K27Me3, pAKT and Ki67, a cell proliferation marker, and an increase in PIK3IP1. These data indicate loss of ARID1A and gain of EZH2 could act in epigenetic concert to promote cancer phenotypes. Taken together, these findings imply that inhibition of the methyltransferase EZH2 represents a novel therapeutic strategy for ARID1A-deficient cancers.
Citation Format: Benjamin Bitler, Azat Garipov, Ie Ming Shih, Rugang Zhang. Targeting EZH2 methyltransferase activity: A novel therapeutic approach to ARID1A-deficient cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B30.
Abstract B49: Histone H3K27 tri-methylation regulates DPYD expression and cellular sensitivity of 5-fluorouracil
Authors: Wu Rentian , Offer Steven , Jerde Calvin , Dunlap Garrett , Diasio Robert 
Published: May 2016

Abstract
Dihydropyrimidine dehydrogenase (DPD) is a major determinant of the efficacy and toxicity of 5-fluorouracil in various cancer therapies. Single nucleotide polymorphisms (SNPs) within DPYD have been studied extensively for years. However, known SNPs do not explain most cases of altered DPD activity and response to 5-FU. Furthermore, variations of DPYD expression in cancer patients have been reported; however, the underlying molecular mechanism is unclear. This suggests that regulation of DPYD expression may be an additional mechanism to control DPD activity. In this study, we focused on epigenetic regulation of DPD and specifically investigated the role of histone methylation on DPYD expression. Inhibition of the H3K27 methyl-transferase Ezh2 by either GSK-126 or a dominant-negative histone H3 mutant significantly increased DPYD expression in various cell lines. The expression of thymidylate synthetase, a major target of 5-fluorouracil toxicity, was not altered. Consistent with elevated DPYD expression, cells that lost H3K27me3 were more resistant to 5-fluorouracil. Furthermore, we demonstrated that Ezh2 and H3K27me3 were enriched on the promoter and the first exon of DPYD in low-DPD expressing cells, but not in cell lines with high DPD levels. Additionally, the enrichment of H3K27me3 on the DPYD promoter was negatively correlated with cellular DPD activity in peripheral mononuclear cells from healthy volunteers. Finally, CRISPR/Cas9-mediated targeting of Ezh2 to the DPYD promoter artificially increased H3K27me3 and suppressed DPYD expression. Collectively, these data suggest that histone methylation can regulate DPYD expression, providing a previously unrecognized mechanism of 5-fluorouracil sensitivity. The tri-methylation of H3K27 is a potential biomarker for guiding individualized 5-FU therapy.
Citation Format: Rentian Wu, Steven Offer, Calvin Jerde, Garrett Dunlap, Robert Diasio. Histone H3K27 tri-methylation regulates DPYD expression and cellular sensitivity of 5-fluorouracil. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B49.
Abstract IA01: Epigenetic mechanisms of tumor initiation and evolution
Authors: Bernstein Bradley E. 
Published: May 2016

Abstract
The paramount importance of epigenetic regulation in cancer is now well established by a convergence of data from cancer genome sequencing, epigenomics and the transcriptional and molecular characterization of tumors and models. Our laboratory research is focused on characterizing epigenetic mechanisms of tumor initiation, as well as on understanding how epigenetic changes and intratumoral heterogeneity contribute to drug resistance and tumor relapse. We are particularly interested in brain tumors as clinically compelling models for investigating epigenetic mechanisms of tumorigenesis. I will present two ongoing projects in this area. The first project is focused on genetic mutations that affect epigenetic regulators and processes, and are associated with gliomagenesis. Here I will discuss our progress towards delineating specific mechanisms, regulatory targets and programs that explain the tumorigenicity of individual mutations. The second project is focused on epigenetic mechanisms that enable glioblastoma stem cells to adapt to environmental stressors or drug pressures. Here we have identified a specific role for histone demethylases in resetting the epigenetic landscapes of glioblastoma stem cells, and thereby allowing them to transition to a more primitive and refractory state. These respective studies exemplify ongoing research in our lab as well as in the broader research community, and have general relevance for cancer biology, diagnosis and therapy.
Citation Format: Bradley E. Bernstein. Epigenetic mechanisms of tumor initiation and evolution. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA01.
Abstract IA05: Genome-wide views into the mechanisms of transcription regulation
Authors: Lis John T. , Danko Charles , Duarte Fabiana , Mahat Dig Bijay 
Published: May 2016

Abstract
RNA Polymerase II (Pol II) is the molecular machine that transcribes all the protein-encoding mRNAs as well as a spectrum of non-coding regulatory RNAs. The distribution of Pol II reveals not only location and levels of transcription of these transcribed genes, but also, the distinctive patterns of divergent transcription that can be used to identify the active promoters and enhancers that regulate these genes. Moreover, by monitoring changes in the distribution of Pol II across genomes in response either to regulatory signals and to directed perturbations of transcription factors, the distinct steps in transcription that are regulated can be elucidated. With increasing positional and temporal resolution provided by new, genome-wide nuclear run-on and chromatin assays, we are able to gain critical insights into the mechanisms governing how polymerases initiate and elongate through transcription units, and into how these processes are regulated. In this presentation, I will provide a comprehensive genome-wide view of the rapid and dramatic changes in transcription that accompany the stress response, a long used model for studying regulation, and the factors and molecular mechanisms that regulate this reprogramed transcriptional response in both Drosophila and mammals.
Citation Format: John T. Lis, Charles Danko, Fabiana Duarte, Dig Bijay Mahat. Genome-wide views into the mechanisms of transcription regulation. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA05.
Abstract IA12: Long-range gene regulation in the context of chromatin domains
Authors: Dekker Job 
Published: May 2016

Abstract
The 3D organization of the genome is critical for gene regulation, genome stability and faithful transmission of chromosomes to daughter cells. We apply Chromosome Conformation Capture-based technologies to determine how cells fold their chromosomes and to discover the mechanisms that drive the spatial organization of genomes. I will discuss our recent proposal that in interphase nuclei mammalian chromosomes are hierarchically organized (Gibcus and Dekker, 2013). First, at the nuclear level, chromosomes are compartmentalized into large multi-Mb domains that are either active and open or inactive and closed. These compartments themselves are composed of smaller sub-Mb Topologically Associating domains (TADs) (Dixon et al. 2012, Nora et al. 2012). Finally, long-range gene regulation occurs within TADs through long-range looping interactions between genes and regulatory elements.
TAD organization and their role in gene regulation have important implications in cancer cells. I will highlight how genomic rearrangements in cancer genomes can lead to altered TAD organization and inappropriate gene expression, including increased expression of cancer promoting genes, and repression of cancer suppressing genes.
I will also highlight two new studies from my laboratory that reveal different roles of TADs in chromosome-wide gene regulation along the dosage compensated X-chromosomes. First, in C. elegans we find that a Condensin complex mediates TAD formation and dosage compensation. Second, in mouse the dosage compensated X chromosome folds in a unique way with global loss of TADs.
Citation Format: Job Dekker. Long-range gene regulation in the context of chromatin domains. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA12.
Abstract PR02: Transcriptional regulation mediated by biochemically distinct forms of SWI/SNF
Authors: Raab Jesse R. , Resnick Samuel , Magnuson Terry 
Published: May 2016

Abstract
Background: We often consider the SWI/SNF complex as a single entity with a single function in a particular cell type. This model ignores that multiple positions within the SWI/SNF chromatin remodeling complex can be filled by mutually exclusive subunits. Inclusion or exclusion of such subunits gives rise to an array of biochemically distinct chromatin remodeling complexes, some of which have profound functional consequences on gene regulation and differentiation. Here, we examine the functional relationships among three complex-specific ARID (AT-Rich Interacting Domain) subunits of the SWI/SNF complex in a human hepatocellular carcinoma cell line using ChIP-seq, RNA-seq, and public data on transcription factor binding.
Results: Using RNAi directed at each of the three subunits, we identify widespread overlap in transcriptional regulation mediated by SWI/SNF. The ARID subunits are commonly bound together at the promoters of active genes, with more variable binding associated with distal regulatory elements. ARID1B and ARID2 cooperate to repress the expression of hundreds of genes. Additionally, we identify many examples of competitive interactions between ARID1A and ARID1B or ARID2, and show that gene expression changes following loss of one ARID are dependent on the function of an alternative ARID. These distinct regulatory modalities are correlated with differential occupancy by transcription factors. Together these data suggest distinct SWI/SNF complexes dictate gene-specific transcription through interactions between different forms of SWI/SNF and specific co-factors. The ARID subunits are among the most frequently mutated chromatin regulators in cancer. Understanding the functional relationship between distinct forms of the complex is a necessary first step for identifying their potentially unique roles in oncogenesis.
Citation Format: Jesse R. Raab, Samuel Resnick, Terry Magnuson. Transcriptional regulation mediated by biochemically distinct forms of SWI/SNF. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr PR02.