bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A35: SMARCE1 mutations cause inherited multiple spinal meningiomas
Authors: Smith Miriam J. , O'Sullivan James , Bhaskar Sanjeev S. , Hadfield Kristen D. , Poke Gemma , Caird John , Sharif Saba , Eccles Diana , FitzPatrick David , Rawluk Daniel , Plessis Daniel du , Newman William G. , Evans D. Gareth 
Published: August 2014

Abstract
Meningiomas represent approximately one third of all primary central nervous system tumors in adults. Multiple meningiomas are usually associated with neurofibromatosis type 2 (NF2) disease, which is caused by mutations in the NF2 gene. Recent reports have also shown multiple meningiomas to be associated with schwannomatosis disease, which is caused by mutations in the SWI/SNF chromatin remodeling complex subunit, SMARCB1. In a subset of individuals, multiple meningioma disease is a discrete entity, inherited in an autosomal dominant manner unrelated to NF2 or SMARCB1 mutations.
We sought to discover novel genes associated with a predisposition to meningioma development by exome sequencing of germline DNA three unrelated individuals with familial multiple spinal meningiomas, who did not have germline NF2 or SMARCB1 mutations.
Two of these three individuals harbored heterozygous novel loss-of-function mutations in the SWI/SNF complex subunit, SMARCE1. Sanger sequencing of SMARCE1 in lymphocyte DNA from six additional individuals with spinal meningiomas identified another two novel heterozygous loss-of-function mutations. Tumors from individuals with germline SMARCE1 mutations were demonstrated a clear cell histological subtype and all demonstrated loss of SMARCE1 protein consistent with a tumor suppressor mechanism.
Our findings define multiple spinal meningioma disease as a novel discrete entity and implicate the SWI/SNF chromatin remodeling complex in the pathogenesis of meningiomas and tumors with clear cell histology.
Citation Format: Miriam J. Smith, James O'Sullivan, Sanjeev S. Bhaskar, Kristen D. Hadfield, Gemma Poke, John Caird, Saba Sharif, Diana Eccles, David FitzPatrick, Daniel Rawluk, Daniel du Plessis, William G. Newman, D. Gareth Evans. SMARCE1 mutations cause inherited multiple spinal meningiomas. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A35.
Abstract A58: Systematic optimization of key parameters involved in the preparation of chromatin and the chromatin immunoprecipitation (ChIP) workflow
Authors: Cooke Tracy , Li Zirong , Saito Kan , Sturges Michael R. , Taganov Konstantin , Thyagarajan Bhaskar , Rosenfeld John M. , Solache Alejandra 
Published: August 2014

Abstract
The ChIP protocol is a fundamental tool that has been used to gain insight into the impact of epigenetic phenomenon and their effect on cancer development and progression. Despite the abundance of research tools that support ChIP, very little innovation has occurred around the ChIP method itself to make the process more reproducible and reliable. Issues surrounding antibody specificity and performance, lack of reliable high-throughput options for limited amounts of chromatin, and accepted criteria to make determinations on the quality of chromatin suitable for ChIP are just some of the challenges faced when performing this method. Improvements in the ChIP process would enable more reliable high resolution genomic mapping of chromatin events that are critical to unambiguously dissect epigenetic regulatory mechanisms and their influence on gene expression.
To address these issues, we have engaged in an iterative process of examining multiple parameters that influence ChIP data. For chromatin fragmentation, we prepared chromatin on a variety of devices and utilized various buffer systems to develop an approach to optimize this process. To allow rapid and evaluation of histone antibody specificity, we have produced tools that allow researchers to evaluate specificity utilizing a simple dot blot western blotting approach. In addition, we have developed low-cell protocol that simplifies the ChIP process, reduces variability and significantly improve signal-to-noise ratios. This protocol has been demonstrated to work in both a low throughput version as well as a high-throughput version that is amenable to automation. Our approach is well suited to those with limited experience in ChIP, but is also sufficiently robust and flexible to enable ChIP from either abundant or limited amounts of chromatin derived from cells or tissues. Using this systematic approach, we present data comparing the impact of different sonication protocols on ChIP, analysis of user-to-user variation, as well as approaches to optimize and control for factors that introduce variability in ChIP.
Citation Format: Tracy Cooke, Zirong Li, Kan Saito, Michael R. Sturges, Konstantin Taganov, Bhaskar Thyagarajan, John M. Rosenfeld, Alejandra Solache. Systematic optimization of key parameters involved in the preparation of chromatin and the chromatin immunoprecipitation (ChIP) workflow. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A58.
Abstract A63: Rsf-1, a chromatin remodeling protein, interacts with shelterin protein hRap1 and induces telomere shortening
Authors: Wu Ren-Chin , Guan Bin , Kobayashi Yusuke , Wang Tian-Li , Shih Ie-Ming 
Published: August 2014

Abstract
Background: Rsf-1, a chromatin remodeling factor that forms an ISWI chromatin-remodeling complex with SNF2H, has been implicated in the oncogenesis of a variety of human cancers, yet its functions in promoting tumor development remains unclear. In this study, we found Rsf-1 interacted with hRap1, a telomere binding protein involved in telomere length regulation. We aimed at characterizing the interaction between Rsf-1 and hRap1 and exploring the effect of Rsf-1 overexpression on telomere length in ovarian cancer cells.
Methods: Protein microarray and co-immunoprecipitation were employed to screen and validate Rsf-1 interaction proteins. Deletion mutants of both Rsf-1 and hRap1 were constructed to map the binding domains responsible for their interaction. To determine whether RSF complex was enriched in the telomeric regions, we performed chromatin immunoprecipitation (ChIP) -qPCR in two ovarian cancer cell lines (OVCAR3 with high RSF-1 gene amplification and Rsf-1 inducible SKOV3) with antibodies against Rsf-1 and SNF2H. A ChIP-sequencing dataset performed with Rsf-1 and SNF2H antibodies using OVCAR3 cells was also examined for enrichment of telomeric sequences. To investigate the effect of Rsf-1 overexpression on telomere length, we evaluated by qPCR the telomere length in two Rsf-1 inducible cell lines (SKOV3 and BRK).
Results: We identified hRap1, a telomere binding protein, as an interaction partner of Rsf-1 by protein microarray and co-immunoprecipitation. Protein interaction domain mapping revealed that C-terminal domain of hRAP1 and PHD domains and arginine-rich region of RSF1 were critical for this interaction. Both ChIP-qPCR and ChIP-sequencing demonstrated that Rsf-1 and SNF2H were enriched in the telomeres, suggesting that RSF complex was recruited by hRAP1 to the telomeres. Induction of RSF1 expression resulted in shortened telomere length in two different cell lines. The results suggest that RSF complex may be involved in the telomere length regulation mediated by hRAP1.
Conclusions: Rsf-1 interacted with hRap1 through the PHD domain and the arginine-rich region. RSF complex bound telomeres, probably through the interaction with hRap1. Rsf-1 overexpression led to telomere length shortening, which may contribute to genomic instability in cancer cells.
Citation Format: Ren-Chin Wu, Bin Guan, Yusuke Kobayashi, Tian-Li Wang, Ie-Ming Shih. Rsf-1, a chromatin remodeling protein, interacts with shelterin protein hRap1 and induces telomere shortening. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A63.
Abstract B24: Ras-mediated epigenetic reprogramming: NF-κB-dependent and independent effects
Authors: Durand Joel , Baldwin Albert 
Published: August 2014

Abstract
In addition to many genetic alterations, cancer cells also harbor global epigenetic abnormalities, a fundamental hallmark of cancer. K-Ras, the most commonly mutated oncogene, has been shown to induce aberrant epigenetic changes, including the methylation and subsequent silencing of key tumor suppressors. Furthermore, in the majority of K-Ras-driven tumors, the NF-κB pathway is constitutively active and contributes to cellular transformation. Specifically, our lab has shown that knocking out the p65 subunit of NF-κB significantly reduces tumor development in a mouse model of K-Ras-induced lung cancer. NF-κB subunits have been shown to associate with HDAC1 and to promote DNMT1 recruitment to chromatin, suggesting the involvement of NF-κB in epigenetic regulation. However, the role of the NF-κB pathway in Ras-mediated epigenetic changes remains unclear. Based on the above, I hypothesize that oncogenic K-Ras cooperates with the NF-κB pathway to alter the epigenetic landscape and promote transformation. Using the Infinium Methylation Assay, we have uncovered genome-wide differences in DNA methylation in lung epithelial cells expressing K-RasG12V (SAKRAS) compared to wild-type (SALEB) cells. Expression of oncogenic K-RasG12V was accompanied by hypermethylation of many tumor suppressors and demethylation of established oncogenes. Notably, many of these changes in methylation correlated with changes in gene expression. Inhibition of the NF-κB pathway in SAKRAS cells also led to significant changes in the methylation profile of a subset of genes. Together, these preliminary results support a role for the K-Ras and NF-κB pathways in the epigenetic reprogramming observed in K-Ras-driven cancers.
Citation Format: Joel Durand, Albert Baldwin. Ras-mediated epigenetic reprogramming: NF-κB-dependent and independent effects. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B24.
Abstract B42: An integrated view on genetic and epigenetic mechanisms revealed aberrant DNA methylation as an important source for miRNA deregulation in prostate cancer
Authors: Bogatyrova Olga , Wuttig Daniela , Gu Lei , Assenov Yassen , Kuner Ruprecht , Baer Constance , Feuerbach Lars , Gerhäuser Clarissa , Weichenhan Dieter , Schlomm Thorsten , Simon Ronald , Sauter Guido , Sültmann Holger 
Published: August 2014

Abstract
Prostate cancer (PCa) the most common malignant tumor in males and the third leading cause of cancer-related deaths in Western developed countries. The clinical spectrum of PCa ranges from indolent tumors requiring no therapy to highly aggressive and often metastatic diseases. MicroRNAs (miRNAs) have emerged as important regulators in human tumorigenesis and tumor progression during the last decade. miRNA expression is strongly deregulated in many human cancers including PCa. We investigated the contribution of genetic and epigenetic events to the deregulation of miRNAs in PCa by utilizing the profiling data of 19 Early-Onset Pca (EOPC) from International Cancer Genome Consortium (ICGC) (http://www.icgc.org). For 31% (154/491) of the downregulated miRNAs and for 23% (133/578) of the upregulated miRNAs, DNA hyper- and hypomethylation respectively of a promoter region was observed in at least one of the 13 PCa. Deletions were detected for 26% (126/491) of the downregulated miRNAs in at least one sample. We observed a single translocation event leading to disruption of miR-1244-2 from its putative regulatory region that might contribute to expression decrease. We did not detect any SNV within miRNA precursors. Only one miRNA precursor (miR-4307) was amplified in one patient, but the corresponding mature miRNA was not expressed at all. We demonstrated that, among deletions, methylation of miRNA promoters is one of the major mechanisms leading to miRNA silencing or activation, respectively in PCa. 37 miRNA were downregulated by hypermethylation of regulatory regions and 10 miRNAs were upregulated by hypomethylation in both the ICGC EOPC cohort and the validation dataset on 50 prostate cancer and 48 normal prostate tissues. 82% (9/11) of the miRNAs/miRNA clusters analyzed regulate genes that are involved in PI3K/AKT/PTEN signaling, which represents one of the PCa key pathways being deregulated in more than one third of primary PCa.
Note: This abstract was not presented at the conference.
Citation Format: Olga Bogatyrova, Daniela Wuttig, Lei Gu, Yassen Assenov, Ruprecht Kuner, Constance Baer, Lars Feuerbach, Clarissa Gerhäuser, Dieter Weichenhan, Thorsten Schlomm, Ronald Simon, Guido Sauter, Holger Sültmann. An integrated view on genetic and epigenetic mechanisms revealed aberrant DNA methylation as an important source for miRNA deregulation in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B42.
Abstract IA11: The epigenetic stability of pluripotent and somatic cell states
Authors: Hanna Jacob H. 
Published: August 2014

Abstract
The identity of somatic and pluripotent cells can be epigenetically reprogrammed and forced to adapt a new functional cell state by different methods and distinct combinations of exogenous factors. The aspiration to utilize such ex vivo reprogrammed pluripotent and somatic cells for therapeutic purposes necessitates understanding of the mechanisms of reprogramming and elucidating the extent of equivalence of the in vitro derived cells to their in vivo counterparts. I will present and analyze our recent advances toward understanding these fundamental questions, and discuss the role of chromatin remodeling complexes in influencing the characteristics of pluripotency and reprogramming. I will further highlight future possibilities for utilizing epigenetic reprogramming for experimental and theoretical modeling of gene expression regulation, cell fate decisions and early mammalian development.
Citation Format: Jacob H. Hanna. The epigenetic stability of pluripotent and somatic cell states. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr IA11.
Abstract IA16: Reactivating epigenetically silenced genes
Authors: Jones Peter A. 
Published: August 2014

Abstract
Chromatin is inherently refractory to the initiation of transcription and to the binding of regulatory factors. Nucleosomes need to be moved or destabilized from DNA sequences by processes involving remodelers. We have designed a new approach called NOME-Seq which allows us to examine DNA methylation patterns and nucleosomal positioning on individual DNA molecules thus digitizing the analysis of accessible chromatin areas. We have used this approach genome wide to analyze the precise nature and physical sizes of nucleosome depleted regions (NDRs) and examined the effects of mutations in chromatin remodelers on these accessible areas. We have also followed the alterations in chromatin accessibility immediately following drug treatment with DNA demethylation agents. Results from these studies give insights as to the mechanisms of action of the drugs and provide opportunities for future drug development.
Citation Format: Peter A. Jones. Reactivating epigenetically silenced genes. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr IA16.
Abstract IA22: Cancer as a single process of a dysregulated epigenome
Authors: Feinberg Andrew P. 
Published: August 2014

Abstract
Since the discovery of altered DNA methylation in cancer in 1982, most studies of cancer epigenetics have focused on epimutations which could serve as surrogates of mutation. In the past decade, we and our collaborators have been leading efforts to develop whole genome approaches to epigenetic analysis of human disease, that include novel approaches to array-based analysis and whole genome bisulfite sequencing. This has led to the first whole genome bisulfite sequencing methylation map of the cancer genome. Surprising results have been the discovery of CpG island shores and large hypomethylated blocks corresponding to nuclear lamina / heterochromatin regions, and accounting for the vast majority of epigenetic changes in cancer. These results point to the possibility that at least solid tumors represent epigenetically a single process with common molecular characteristic, namely increased epigenetic plasticity that allows selection of the tumor cells at the expense of the host. This view can explain most of the hallmarks of cancer, as well as offering a strategy for powerful new approaches to risk detection and treatment.
Citation Format: Andrew P. Feinberg. Cancer as a single process of a dysregulated epigenome. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr IA22.
Abstract PR05: Reversing the oncogenic roles of misdirected chromatin remodeling: Disruption of mSWI/SNF (BAF) complexes by the SS18-SSX fusion in human synovial sarcoma
Authors: Kadoch Cigall , Crabtree Gerald R. 
Published: August 2014

Abstract
Recent exon- and genome-wide sequencing studies of human cancers have revealed frequent mutations in genes encoding subunits of mSWI/SNF or BAF complexes and implicated them as tumor suppressors. Indeed, we estimate that they are mutated in &gt;20% of human cancers (Kadoch et al, Nature Genetics 2013). Interestingly, the subunits most commonly mutated are not required for chromatin remodeling in vitro and thus may contribute to chromatin regulation in a novel way. One difficultly in understanding the oncogenic role(s) of these complexes is distinguishing primary driving mutations from passenger mutations. To investigate the mechanism underlying oncogenesis, we studied human synovial sarcoma (SS), in which transformation results from a remarkably precise and uniform translocation of exactly 78 amino acids of SSX (SSX1, 2 or 4) to the SS18 protein. In a proteomic study we discovered that SS18 is a dedicated, non-exchangeable subunit of BAF complexes. We demonstrate that the hallmark SS18-SSX fusion incorporates into BAF complexes, evicting both the wild-type SS18 protein and the tumor suppressor, hSNF5 (BAF47), which is known to be biallelically inactivated in malignant rhabdoid tumors. The altered complex binds the Sox2 locus, reversing polycomb-mediated H3K27me3 repression and activating Sox2. Sox2 is uniformly expressed in SS tumors and is essential for proliferation. Remarkably, increasing the concentration of wild-type SS18 leads to reassembly of wild-type complexes, retargeting of BAF complexes, returned polycomb-mediated repression at the Sox2 locus and cessation of SS cell proliferation. This mechanism of transformation depends on a two amino acid hydrophilic region of SSX and hence provides a potential foundation for therapeutic intervention.
Citation Format: Cigall Kadoch, Gerald R. Crabtree. Reversing the oncogenic roles of misdirected chromatin remodeling: Disruption of mSWI/SNF (BAF) complexes by the SS18-SSX fusion in human synovial sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR05.
Abstract PR07: SNF5 is an essential executor of epigenetic regulation during differentiation
Authors: You Jueng Soo , Carvalho Daniel D. De , Dai Chao , Liu Minmin , Pandiyan Kurinji , Zhou Xianghong , Liang Gangning , Jones Peter A. 
Published: August 2014

Abstract
Nucleosome occupancy controls the accessibility of the transcription machinery to DNA regulatory regions and serves an instructive role for gene expression. Chromatin remodelers, such as the BAF complexes, are responsible for establishing nucleosome occupancy patterns, which are key to epigenetic regulation along with DNA methylation and histone modifications. Some reports have assessed the roles of the BAF complex subunits and stemness in murine embryonic stem cells. However, the details of the relationships between remodelers and transcription factors in altering chromatin configuration, which ultimately affects gene expression during cell differentiation, remain unclear. Here for the first time we demonstrate that SNF5, a core subunit of the BAF complex, negatively regulates OCT4 levels in pluripotent cells and is essential for cell survival during differentiation. SNF5 is responsible for generating nucleosomedepleted regions (NDRs) at the regulatory sites of OCT4 repressed target genes such as PAX6 and NEUROG1, which are crucial for cell fate determination. Concurrently, SNF5 closes the NDRs at the regulatory regions of OCT4 activated target genes such as OCT4 itself and NANOG. Furthermore, using loss and gain of function experiments followed by extensive genome-wide analyses including gene expression microarrays and ChIP-sequencing, we highlight that SNF5 plays dual roles during differentiation by antagonizing the expression of genes that were either activated or repressed by OCT4, respectively. Together, we demonstrate that SNF5 executes the switch between pluripotency and differentiation.
This abstract is also presented as Poster A39.
Citation Format: Jueng Soo You, Daniel D. De Carvalho, Chao Dai, Minmin Liu, Kurinji Pandiyan, Xianghong Zhou, Gangning Liang, Peter A. Jones. SNF5 is an essential executor of epigenetic regulation during differentiation. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR07.