bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B20: Malignant transformation initiates a stochastic DNA methylation alteration pattern distinct from that in senescence
Authors: Xie Wenbing , Zhang Yang W. , Pan Li-Xia , Carvlho Fillipe , Kang Byung-Hak , Xia Limin , Murphy Lauren , Zahnow Cynthia A. , Baylin Stephen B. , Easwaran Hari 
Published: May 2016

Abstract
DNA methylation changes are a hallmark of cancers and occur during early tumorigenesis stages. Also, distinct DNA methylation patterns are reported to be characteristic of the anti-tumorigenic process of cell senescence. It is hypothesized that some cells escape senescence and retain the DNA methylation abnormalities manifest in cancers. We now re-visit, in a classic model of tumor progression in human fibroblasts, the relationships between genome-wide DNA methylation patterns associated with senescence, immortalization and transformation. We find that although DNA methylation alterations are a key feature during senescence, these changes are distinct from those we now find associated with malignant transformation in our model and which are classically seen in cancer. Both DNA methylation gains, predominantly at promoter CpG islands, and more balanced losses and gains at other loci, are seen by the time of pre-senescence and remain relatively stable until full senescence is reached. These DNA methylation alterations follow a reproducible pattern amongst independent senescent replicates involving genes in biological processes which positively regulate biosynthesis, gene transcription and macromolecule metabolism. In contrast, during immortalization and malignant transformation, the DNA methylation alterations appear to arise in a stochastic process resulting in heterogeneous methylation patterns amongst independently immortalized and transformed replicates. Gene ontology analysis shows that genes which gain DNA methylation in normally unmethylated promoter CpG island regions in independent transformation replicates enrich for functions involved in developmental regulation. Over the course of progression from immortalization to the transformed state in our model, gene promoter CpG island hypermethylation frequency increases, as does the numbers of associated genes that have decreased gene expression. Thus, a hallmark of the early transformation process is a stochastic accumulation of DNA methylation changes, distinct from those occurring during senescence, that converges to increasingly affect developmental biological processes and diminished transcription of many of the involved genes, which may help drive the process of tumor progression.
Citation Format: Wenbing Xie, Yang W. Zhang, Li-Xia Pan, Fillipe Carvlho, Byung-Hak Kang, Limin Xia, Lauren Murphy, Cynthia A. Zahnow, Stephen B. Baylin, Hari Easwaran. Malignant transformation initiates a stochastic DNA methylation alteration pattern distinct from that in senescence. [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 B20.
Abstract B24: High-dimensional genomic data integration and bias correction using MANCIE
Authors: Zang Chongzhi , Wang Tao , Deng Ke , Li Bo , Hu Sheng'en , Qin Qian , Xiao Tengfei , Zhang Shihua , Meyer Clifford A. , He Housheng Hansen , Brown Myles , Liu Jun S. , Xie Yang , Liu Xiaole Shirley 
Published: May 2016

Abstract
Most genomic and epigenomic experimental data are presented as high-dimensional matrices. Integrative analysis of such high-dimensional genomic data is challenging due to noises and biases in the high-throughput experiments from different platforms. We present MANCIE (Matrix Analysis and Normalization by Concordant Information Enhancement), a computational method for integrating two genomic datasets based on a Bayesian supported principal component analysis (PCA) approach. We demonstrate that data integration using MANCIE can reduce biases and improve the identification of tissue specificity from the Encyclopedia of DNA Elements (ENCODE) data, improve prognostic prediction from The Cancer Genome Atlas (TCGA) data, and improve the identification of genetic correlation in the Cancer Cell Line Encyclopedia (CCLE) data. MANCIE has broad applications in genomic and epigenomic data analysis in cancer research.
Citation Format: Chongzhi Zang, Tao Wang, Ke Deng, Bo Li, Sheng'en Hu, Qian Qin, Tengfei Xiao, Shihua Zhang, Clifford A. Meyer, Housheng Hansen He, Myles Brown, Jun S. Liu, Yang Xie, Xiaole Shirley Liu. High-dimensional genomic data integration and bias correction using MANCIE. [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 B24.
Abstract B29: Inhibition of histone deacetylases 1 and 2 (HDAC1,2) perturbs DNA replication and DNA repair in cancer cells: Implications in mechanism-based therapeutic strategies
Authors: Johnson Danielle , Jones Simon , Quayle Steven , Shearstone Jeff , Bhaskara Srividya 
Published: May 2016

Abstract
Class I family enzymes, histone deacetylases 1 and 2 (HDAC1,2), are targets of FDA-approved small molecule inhibitors currently used in cancer therapy. HDAC inhibitors impair DNA repair and replication in cancer cells to trigger genotoxic stress and cause cell death. How HDAC1,2 function in genome maintenance processes, DNA replication and repair, in mammalian cells is far from fully understood. Using small molecules to selectively inhibit HDAC1,2 activities, we have systematically defined their direct functions in DNA replication and repair. Our studies show that HDAC1,2 inhibition reduces replication fork velocity and activates the replication stress associated DNA damage independent of its effect on transcription. HDAC1,2 inhibition increases histone H4K16 acetylation (H4K16ac) and nuclease sensitivity of nucleosomes associated with newly replicated DNA, suggesting that HDAC1,2 are required for chromatin compaction during DNA replication. Thus, mechanistically, HDAC1,2 activities are required for maintaining nascent chromatin structure and dynamics required for efficient progression of the replication fork. In addition to H4K16ac, we have found that HDAC1,2 inhibition activities increases H3K27ac and H4K91ac present on the histone tail and core regions, respectively. Increase in these histone acetyl marks perturbs the acetyl-methyl or the acetyl-ubiquityl switch during DNA repair leading to impaired EZH2-mediated H3K27me3-dependent DNA repair signaling and the H4K91ubiquityl-dependent 53BP1-mediated DNA repair signaling in chemoresistant EZH2 gain-of-function diffuse large B-cell lymphoma cells. We are currently investigating the therapeutic benefits of HDAC1,2 inhibition in mouse models of aggressive chemoresistant diffuse large B-cell lymphoma and in primary patient samples. Overall, our studies have uncovered novel functions for HDAC1,2 in genome maintenance processes and provide insight into the mode-of-action of HDAC1,2 inhibitors in overcoming chemoresistance in cancer cells (via targeting the DNA repair process) and in inducing DNA damage and death in the rapidly cycling cancer cells (via targeting DNA replication).
Note: This abstract was not presented at the conference.
Citation Format: Danielle Johnson, Simon Jones, Steven Quayle, Jeff Shearstone, Srividya Bhaskara. Inhibition of histone deacetylases 1 and 2 (HDAC1,2) perturbs DNA replication and DNA repair in cancer cells: Implications in mechanism-based therapeutic strategies. [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 B29.
Abstract B43: Dose and context-dependent roles for Arid1a in liver tumorigenesis
Authors: Sun Xuxu , Wang Sam , Nguyen Liem , Zhu Hao 
Published: May 2016

Abstract
Frequent Arid1a loss-of-function mutations suggest tumor suppressive roles, but the functional impact of Arid1a and SWI/SNF chromatin-remodeling aberrations in human cancer are not clear. Liver-specific Arid1a knockout mice do not develop cancer after 15 months and surprisingly, homozygous mice are potently protected from diethylnitrosamine (DEN) + carbon tetrachloride induced hepatocellular carcinoma (HCC). This is likely due to the fact that Arid1a deficient livers are resistant to chemical damage in a Cytochrome P450 dependent fashion. To determine if genetic drivers of cancer might reveal additional roles for Arid1a, we showed that Arid1a loss results in increased survival in a MYC driven liver cancer model. Given the physical interactions between MYC and Arid1a and a global reduction in mRNA levels, we hypothesize that MYC's transcriptional activities are constrained by the lack of normal SWI/SNF chromatin remodeling. Interestingly, in vivo anti-Arid1a siRNA delivery to mice overexpressing MYC also prolonged survival, demonstrating that mutation timing does not explain the lack of tumor suppressor activity. Our models build the case that Arid1a is not a bona fide tumor suppressor gene in many important contexts.
Citation Format: Xuxu Sun, Sam Wang, Liem Nguyen, Hao Zhu. Dose and context-dependent roles for Arid1a in liver tumorigenesis. [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 B43.
Abstract B44: Accelerated mouse colorectal cancer progression in the presence of EHMT2 overexpression
Authors: Tai Kang-Yu , Yu I-Shing , Cha Shih-Ting , Lin Shu-Wha , Kuo Min-Liang , Chen You-Tzung 
Published: May 2016

Abstract
In the last 5 years, the prevalence of colorectal cancer (CRC) has increased worldwide and has surpassed that of liver cancer. Even after treatment for primary CRC, patients still have a high risk (30%–50%) of cancer recurrence, generally from metastasis. Thus, if we can uncover the progressive mechanisms of CRC and identify a novel drug target, current treatment regimens and the survival of patients with advanced stage CRC can be improved. Euchromatin histone lysine N-methyl transferase 2 (EHMT2) inhibition is considered an effective therapeutic strategy for cancer treatment because its inhibitors, BIX-01294 and UNC0639, can induce autophagy-dependent cell death. However, the function of EHMT2 in CRC progression remains largely unclear. In this study, we established a colonic stem-cell-specific EHMT2 activation combined with sporadic (AOM/DSS-induced) or hereditary (Apc mutant) CRC mouse models. In the EHMT2-overexpressed group, many colonic tumors larger than 3 mm in size were found in the 24 weeks after tumor induction. Histological analysis of these tumors showed that the adenocarcinomatous glands became highly irregular, and these glands were difficult to discern, one of the characteristic of malignant CRC. In the 52 weeks after tumor induction, we reproducibly observed CRC liver metastases. Further analysis by RNA sequencing combined with gene set enrichment analysis determined that the anti-apoptosis-related and Wnt-signaling gene sets can be enriched in the EHMT2-overexpressed group. Using the chromatin immunoprecipitation assay, we demonstrated that EHMT2 directly targeted the caspase8 proximal promoter region and increased the level of H3 lysine9 di-methylation in this region. Several functional assays supported that this gene regulation may have conferred opportunities for CRC cells to avoid the cytotoxicity of anticancer drugs. Overall, aberrant EHMT2 expression is conducive to CRC progression.
Citation Format: Kang-Yu Tai, I-Shing Yu, Shih-Ting Cha, Shu-Wha Lin, Min-Liang Kuo, You-Tzung Chen. Accelerated mouse colorectal cancer progression in the presence of EHMT2 overexpression. [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 B44.
Abstract B48: Epigenetic reprogramming of mitochondrial and metabolic functions plays a key role in arginine-deprivation based cancer therapy
Authors: Wang Hung-Jung , Yu Yen-Ling , Hsu Sheng-Chieh , Kuo Cheng-Chin , Wang Wen-Ching , Shuu Chin-Pin , Kung Hsing-Jien 
Published: May 2016

Abstract
Arginine deprivation has recently emerged as a promising cancer therapy, targeting tumor metabolism. This is due to the selective silencing of argininosuccinate synthetase 1 (ASS1) gene in many cancer types, rendering them “addicted” to external arginine. PEGylated arginine deiminase (ADI-PEG20), which effectively metabolizes arginine into citrulline and ammonia, has shown promising results in clinical trials for treating a variety of cancers. We have previously shown that ADI-PEG20 induces a novel type of tumor cell killing involving mitochondria dysfunction and chromatin autophagy, and that lysine demethylase KDM8 which regulates PKM2 plays an important role in tumor metabolism. We also observed in ADI-treated cells, the severe depletion of metabolites involved in glycolysis and glutaminolysis including alpha-ketoglutarate, a key cofactor for many of the KDMs. In parallel, many of the metabolic genes and nuclear genes involved in TCA cycles are coordinately down-modulated, which can be rescued by the addition of arginine. To study whether the coordinated gene repression is via epigenetic mechanism or due to the inhibition of KDMs, we analyzed the methylation status of histones at the promoter sites of metabolic genes, and found consistent accumulation of histone marks associated with transcriptional repression in ADI-PEG20-treated cells. Our results thus suggest that epigenetic reprogramming plays an important a role in the coordinated repression of metabolic gene expression in arginine-deprived cells.
Citation Format: Hung-Jung Wang, Yen-Ling Yu, Sheng-Chieh Hsu, Cheng-Chin Kuo, Wen-Ching Wang, Chin-Pin Shuu, Hsing-Jien Kung. Epigenetic reprogramming of mitochondrial and metabolic functions plays a key role in arginine-deprivation based cancer therapy. [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 B48.
Abstract IA02: Genomic organization of yeast chromatin and gene regulatory complexes
Authors: Pugh B. Franklin 
Published: May 2016

Abstract
The large number of genes across eukaryotic genomes begs the question as to whether they are all fundamentally regulated in the same manner. Clearly, sequence-specific factors direct gene-specific regulation, but then do all downstream events proceed along a common path? To begin to address this question, we use ChIP-exo to map the precise contact points of proteins along genomic DNA. The near single-bp readout provides structural insights into how proteins are organized into complexes across genomes, and how they might position nucleosomes to regulate gene expression. Multiple classes of complexes occupy nucleosome-free promoter regions: an ensemble of sequence-specific factors and their coactivators, the core transcription machinery, chromatin remodelers and nucleosomes. This talk will focus on identifying common principles that determined how factors and chromatin organize themselves at promoters across co-regulated genes, and in genes in general.
Citation Format: B. Franklin Pugh. Genomic organization of yeast chromatin and gene regulatory complexes. [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 IA02.
Abstract IA04: How DNA methylation organizes the cancer epigenome
Authors: Jones Peter A. 
Published: May 2016

Abstract
The holistic role of DNA methylation in the organization of the cancer epigenome is not well understood. We performed a comprehensive, high-resolution analysis of chromatin structure to compare the landscapes of HCT116 colon cancer cells and a DNA methylation deficient derivative. The NOMe-seq accessibility assay unexpectedly revealed symmetrical and transcription-independent nucleosomal phasing across active, poised and inactive genomic elements. DNA methylation abolished this phasing primarily at enhancers and CpG Island (CGI) promoters, with little effect on insulators and non-CGI promoters. Abolishment of DNA methylation led to the context-specific reestablishment of the poised and active states of normal colon cells, which were marked in methylation-deficient cells by distinct H3K27 modifications and the presence of either well-phased nucleosomes or nucleosome depleted regions, respectively. Taken together, our results demonstrate the nuanced and context-dependent role of DNA methylation in the functional, multi-scale organization of cancer epigenomes.
Citation Format: Peter A. Jones. How DNA methylation organizes the cancer epigenome. [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 IA04.
Abstract IA10: Regulating transcription elongation at stimulus responsive genes
Authors: Adelman Karen , Scruggs Benjamin S. , Henriques Telmo , Burkholder Adam , Fargo David C. 
Published: May 2016

Abstract
The majority of mammalian protein-coding genes display transcription in both sense and anti-sense directions. At such bidirectional promoters, Pol II has been shown to initiate transcription and undergo promoter-proximal pausing near both the sense-strand mRNA transcription start site (TSS) and from within the upstream region in the anti-sense direction. This enigmatic, dual promoter structure raises fundamental questions about the specificity, purpose and regulation of upstream anti-sense transcription. Interestingly, transcription in the anti-sense direction is generally non-processive and creates short, unstable non-coding RNAs (ncRNAs). Intriguingly, many distal enhancer regions display bidirectional transcription and generate short unstable ncRNAs, raising parallels between enhancers and anti-sense promoters near protein-coding genes.
Importantly, enhancers and upstream anti-sense promoters show exquisite cell type specificity in their location and activity, suggesting key roles in establishing cell state and behavior. Further, perturbation of either transcription or chromatin structure at such non-coding loci has been implicated in the development of cancer and disease, with a profound impact on maintenance of cell state and responsiveness to stimuli. These recent findings raise a number of intriguing questions about the communication between promoters and non-coding loci.
Our work has recently defined a mechanism through which upstream anti-sense transcription impacts stimulus-responsive gene expression. Specifically, we found that the distance between sense and anti-sense TSSs at bidirectional promoters strongly influences activation of pro-inflammatory genes in macrophages. We discovered that anti-sense TSSs organize chromatin structure, creating a region of open chromatin between bidirectional TSSs that is optimal for recruitment of the transcription machinery and signal-dependent transcription factors like NF-kB. Further, we discovered that key inflammatory genes possess enhancer-like histone modifications around the anti-sense TSS, and that this characteristic selectively marks genes that are highly activated upon immune stimulation.
Citation Format: Karen Adelman, Benjamin S. Scruggs, Telmo Henriques, Adam Burkholder, David C. Fargo. Regulating transcription elongation at stimulus responsive genes. [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 IA10.
Abstract PR04: Targeting super-enhancer driven oncogene transcription through cyclin-dependent kinase inhibitors
Authors: Krajewska Malgorzata , Moore Nathan F. , Chipumuro Edmond , Zhang Tinghu , Marco Eugenio , Hatheway Clark , Sharma Bandana , Kwiatkowski Nicholas , Yuan Guo-Cheng , Young Richard A. , Gray Nathanael S. , George Rani E. 
Published: May 2016

Abstract
Cyclin-dependent kinases (CDKs) with primary roles in transcription regulation are emerging as tractable therapeutic targets in cancers driven by the aberrant expression of oncogenic transcription factors. Our goal is to disrupt the myriad and pleomorphic features of oncogenic MYC through inhibiting CDKs involved in its transcriptional amplifier role. CDK7 participates in transcription initiation by phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase (Pol) II and also functions as a CDK-activating kinase, while CDK12 functions in transcription elongation and RNA processing. Using a novel covalent CDK7 inhibitor, THZ1, we demonstrated striking activity and selectivity in neuroblastoma (NB) cells driven by high MYCN expression. This response translated to significant tumor regression in a mouse model of high-risk NB, without introducing discernible toxicity. We determined that this effect was associated with global inhibition of MYCN-dependent transcriptional amplification. THZ1 led to preferential downregulation of Pol II occupancy at super-enhancer-associated genes, including MYCN and other master transcription factors critical to neuronal development such as PHOX2B, GATA2, and DBH. Similarly, inhibition of CDK12 activity using a novel, first-in-class small molecule inhibitor, THZ-5-31-1, resulted in potent antitumor activity in MYCN-overexpressing NB cells. THZ-5-31-1 doses sufficient to induce PARP cleavage did not lead to significant inhibition of global transcription elongation. Rather, cytotoxicity was associated with preferential downregulation of RNA processing factors and a higher percentage of immature mRNA transcripts. Together, these results suggest that transcriptional CDK inhibitors, by affecting different aspects of the transcription machinery, may inhibit the growth of cancers driven by oncogenic transcription factors such as MYC.
Citation Format: Malgorzata Krajewska, Nathan F. Moore, Edmond Chipumuro, Tinghu Zhang, Eugenio Marco, Clark Hatheway, Bandana Sharma, Nicholas Kwiatkowski, Guo-Cheng Yuan, Richard A. Young, Nathanael S. Gray, Rani E. George. Targeting super-enhancer driven oncogene transcription through cyclin-dependent kinase inhibitors. [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 PR04.