bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B32: Dynamic whole-genome methylomes reveal hidden diversity of CpG islands at multiple biological levels
Authors: Zeng Jia , Nagrajan Hema , Yi Soojin V. 
Published: August 2014

Abstract
CpG islands mark epigenetic regulatory hotspots of mammalian genomes. Numerous studies have demonstrated essential roles of CpG islands in regulation of gene expression, developmental processes, genomic imprinting, aging, and cancer. These regulatory effects rest critically on correct (or the lack of) DNA methylation of CpG islands, and aberrant DNA methylation of CpG islands are hallmarks of cancer. However, how DNA methylation of CpG islands occurs across different cell types, and how variation of CpG islands methylation relates to their functions, remain poorly understood. Here we present a global analysis of DNA methylation of CpG islands in the human genome. We examined variation of CpG island methylation across five complete methylomes of distinctive origins (whole blood, prefrontal cortex, sperm, embryonic stem cells and fibroblast). Our goal was to identify distinctive characteristics of CpG islands with respect to their epigenetic variation in normal tissues. Our analysis reveals that, contrary to the prevailing notion, CpG islands mark the most highly variably methylated regions in the human genome. Many CpG islands exhibit highly methylome-specific patterns of DNA methylation. Remarkably, DNA methylation patterns of CpG islands reflect their distinctive nature at many biological levels, including genomic characteristics such as lengths and nucleotide composition, functional differences as evidenced by distinctive gene ontology enrichments, and evolutionary features. Moreover, CpG islands implicated in cancers and those associated with aging show intriguing differences in their genomic, epigenomic and functional features. These findings indicate distinctive nature of CpG islands at genomic, epigenomic and functional levels. These new knowledge provides novel insights into deciphering the regulatory mechanisms of CpG islands in human health and diseases and may be used to improve empirical studies of DNA methylation variation across different biological conditions, and furthermore ultimately to aid development of better diagnostic markers.
Note: This abstract was not presented at the conference.
Citation Format: Jia Zeng, Hema Nagrajan, Soojin V. Yi. Dynamic whole-genome methylomes reveal hidden diversity of CpG islands at multiple biological levels. [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 B32.
Abstract B39: Methylation of BRCA2 gene promoter CpG units through ZAR2-dependent DNMT1 recruitment
Authors: Misra Smita , Mittal Mukul K. , Khedkar Sheetal V. , Chaudhuri Gautam 
Published: August 2014

Abstract
BRCA2 gene expression is stringently regulated during the cell cycle. BRCA2 expression is proportional to the rate of cell proliferation. Looking at the human BRCA2 gene minimal promoter sequence we found that it has over 45 CpG units which could be potentially methylated regulating the recruitment of different transcription factors affecting BRCA2 gene expression. We discovered that BRCA2 gene promoter has bi-directional activity and the product of the reverse activity (a ZAR1-like protein, we named ZAR2) silences the forward promoter (for BRCA2). ZAR2 is a C4-type zinc finger-containing transcription factor that regulates BRCA2 in a cell cycle dependent manner. We found that ZAR2 enters the nucleus of the G0/G1 cells binds to the promoter of BRCA2 and silences the BRCA2 gene expression. ZAR2 has a dsRNA binding domain. We report here that BRCA2 gene promoter, through its bidirectional activity, produces two partially overlapping transcripts (BRCA2 and ZAR2) in the breast cells forming a 111 bp RNA duplex. We postulate that endogenous transcriptional gene silencing RNAs (tgsRNAs) against BRCA2 gene promoter are thus formed from the overlapping RNA duplex in the cell nucleus. These tgsRNAs in turn contribute towards promoter methylation. Our data suggest that ZAR2 upon binding to the tgsRNAs binds to specific locations of BRCA2 gene promoter and recruits DNMT1 which in turn perform CpG methylation. This study will contribute towards the understanding of the epigenetic regulation of BRCA2 gene expression in different cell cycle stages as well as in sporadic cases of breast and other cancer. Supported in part by the DOD-CDMRP IDEA Grants BC990678 and BC050641 to GC and MeTRC pilot project grant 1U54RR026140-01 to SM
Citation Format: Smita Misra, Mukul K. Mittal, Sheetal V. Khedkar, Gautam Chaudhuri. Methylation of BRCA2 gene promoter CpG units through ZAR2-dependent DNMT1 recruitment. [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 B39.
Abstract B40: Methylation signatures specific to triple negative breast cancer subtypes
Authors: Kowalski Jeanne , Switchenko Jeffery M. , Dwivedi Bhakti , Nickleach Dana , Moreno Carlos S. 
Published: August 2014

Abstract
Objective: We identify methylation signatures specific to triple negative breast cancer (TNBC) subtypes using publicly available data, and examine their association with expression.
Materials and Methods: DNA methylation, RNAseq expression and clinical data from breast invasive carcinoma patients were obtained from The Cancer Genome Atlas (TCGA) Data portal. The classification of each patient sample as TNBC was defined according to a combination of FISH and/or IHC results for ER, PR and HER2 negativity. Each TNBC specimen was classified into one of the following molecular subtypes by applying the gene expression-based model of Lehman (2011): basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (MES), mesenchymal stem-like (MSL), luminal androgen receptor (LAR), and unstable (UNS). Among the 116 identified TNBC specimens, 61 had level-three data available on both methylation and RNAseq expression. For methylation, beta values were extracted based on Illumina's Infinium Human DNA Methylation 450K platform; for expression, RNAseqV2 Expectation/Maximization normalized counts (RSEM: Li and Dewey, 2011) were extracted on 20,531 genes and a logarithmic transformation applied. Data were filtered to identify methylation changes specific to each TNBC subtype based on a novel, generalized statistic (Switchenko and Kowalski, 2013) and tested for median difference between subtypes using p &lt; 0.10 to define significance.
Results: Among the 61 TNBC samples, the following molecular subtypes were represented: BL1 (n=6), BL2 (n=6), IM (n=12), LAR (n=5), MES (n=15), MSL (n=4), and UNS (n=13). A number of genes were determined to be hypermethylated with corresponding decreased expression by RNAseq in several subtypes. Methylated genes specific to the LAR TNBC subtype included IGF1R (61% LAR vs. 2% other) and N4BP2L1 (44% LAR vs. 3% other). Methylated genes in the MES subtype included ACSL5 (80% vs. 50%), RHOH (82% vs. 6%) and OAS2 (26% vs. 7%), and specific to the BL2 subtype were EN1 (35% vs. 8%) and TRAFIP3 (60% vs. 35%). Two hypomethylated genes, PIK3CD and CD69, associated with respective subtypes, MSL and IM, showed corresponding increased expression levels.
Conclusion: Our results provide further insight into the molecular heterogeneity surrounding TNBC patients by examining methylation changes specific to molecular subtypes, which may be further examined for their effect on clinical outcome.
Citation Format: Jeanne Kowalski, Jeffery M. Switchenko, Bhakti Dwivedi, Dana Nickleach, Carlos S. Moreno. Methylation signatures specific to triple negative breast cancer subtypes. [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 B40.
Abstract B64: Conglomerate methylation silencing of clustered proto-cadherin genes in the course of cervical carcinogenesis
Authors: Chu Tang-Yuan , Wang Kai-Hung , Lin Cuei-Jyuan 
Published: August 2014

Abstract
Objective: A common phenomenon in cancer invasion involves global epigenetic remodeling of cell adhesion genes. Taking the advantage of the discrete spectrum of lesions in cervical carcinogenesis, this study aims to discover and characterize globally methylated cell adhesion genes in the early invasion period of cervical carcinogenesis.
Methods: Genome-wide methylation array was performed on 36 cervical intraepithelial neoplasia (CIN) 3/ early invasive cancer (CA) and 36 normal/inflammation/CIN1 specimens. Methylation silencing was validated in cancer cells and cohort specimens by bisulfite sequencing, methylation specific PCR, RT-PCR and 5-Aza-dC treatment.
Results: Widespread methylation silencing of 12 members of clustered protocadherin (PCDH) genes including PCDHA4, PCDHA8, PCDHA10, PCDHA13, PCDHB3, PCDHB6, PCDHB7, PCDHB14, PCDH GA12, PCDHGB6, PCDHGB7 and PCDHGC3 was discovered and validated. These PCDH genes were collectively silenced by methylation in differing spectra in a wide variety of cancer cells including carcinoma of the cervix (4/4 cell lines), endometrium (2/2), liver (3/3), head and neck (3/3), breast (1/3), and lung (1/2). In an independent cohort of the spectrum of cervical neoplasia including 60 normals, 30 CIN1, 20 CIN2/3 and 80 CA, methylated PCDHA13 was noted in 17%, 58%, 69% and 78%, respectively (P&lt;10-11).
Conclusions: Methylation silencing of clustered PCDH genes is a general phenomenon of carcinomas. Methylation of members of this gene family can be valuable diagnostic markers in detection of cancers as exemplified by methylated PCDHA13 in cervical cancer.
Citation Format: Tang-Yuan Chu, Kai-Hung Wang, Cuei-Jyuan Lin. Conglomerate methylation silencing of clustered proto-cadherin genes in the course of cervical carcinogenesis. [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 B64.
Abstract IA01: Transcriptional and epigenetic control of oncogenes
Authors: Young Richard A. 
Published: August 2014

Abstract
The gene expression program of any particular cell largely defines its identity and its functions. I will describe new insights into the roles that transcription factors and chromatin regulators play in the control of gene expression programs during normal development and in cancer. These insights provide opportunities for the development of novel therapeutics for cancer and other diseases.
Citation Format: Richard A. Young. Transcriptional and epigenetic control of oncogenes. [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 IA01.
Abstract IA07: New functions for histone modifying enzymes
Authors: Dent Sharon Y.R. , Atanassov Boyko , Hirsch Calley , Koutelou Evangelia , Latham John 
Published: August 2014

Abstract
Histone modifying enzymes are important creating and maintaining epigenetic programs that regulate cell identity and growth. Mutations or abnormal expression of these proteins are associated with multiple cancers. Our lab uses genetic approaches to define the full spectrum of functions for these enzymes. For example, we have created a series of mutations in the mouse Gcn5 gene in order to define the functions of this histone acetyltransferase (HAT) in a mammalian system. Deletion of Gcn5 led to early embryonic death and to telomere dysfunction. Biochemical studies revealed that depletion of Gcn5 or ubiquitin specific protease 22 (Usp22), which is another bona fide component of the Gcn5-containing SAGA-type complex, increases the turnover of two shelterin proteins, TRF1 and POT1a (Atanassov, 2009). Our studies provided the first indication that Gcn5 and mammalian SAGA influence telomere maintenance and the first demonstration that SAGA affects protein stability. We are now defining the role of Gcn5 and SAGA in maintenance of pluripotency in ES cells and ES cell differentiation. Our data indicate that Gcn5 is an important cofactor for both Myc and E2F family transcription factors. We are also identifying additional USP22 protein substrates and are defining USP22 functions during mouse development.
We have also discovered unexpected functions for the Set1 lysine methyltransferase, which is highly homologous with the MLL protein, during mitosis. We found that Set1 methylates kinetochore proteins, such as Dam1, in yeast, and we have determined that H2Bub is required in trans for methylation of this protein. This work provides the first example of cross talk between a histone modification and a modification in a non-histone protein, defining a new mode of “chromatin signaling.”
Zhang K, Lin W, Latham JA, Riefler GM, Schumacher JM, Chan C, Tatchell K, Hawke DH, Kobayashi R, Dent SY. The Set1 methyltransferase opposes Ipl1 aurora kinase functions in chromosome segregation. Cell 122(5):723-34, 9/2005. PMCID: PMC1794220
Atanassov BS, Evrard YA, Multani AS, Zhang Z, Tora L, Devys D, Chang S, Dent SY. Gcn5 and SAGA Regulate Shelterin Protein Turnover and Telomere Maintenance. Mol Cell 35(3):352-364, 8/2009. PMCID: PMC2749492.
Atanassov BS, Dent SY. USP22 regulates cell proliferation by deubiquitinating the transcriptional regulator FBP1. EMBO Rep 12(9):924-30, 9/2011. e-Pub 9/2011. PMCID: PMC3166460.
Latham JA, Chosed RJ, Wang S, Dent SY. Chromatin signaling to kinetochores: Trans-regulation of Dam1 methylation by histone H2B ubiquitination. Cell 146(5):709-19, 9/2011. PMCID: PMC3168986.
Citation Format: Sharon Y.R. Dent, Boyko Atanassov, Calley Hirsch, Evangelia Koutelou, John Latham. New functions for histone modifying enzymes. [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 IA07.
Abstract IA08: Targeting histone methylation in leukemia
Authors: Armstrong Scott A. 
Published: August 2014

Abstract
Leukemias harboring rearrangements of the MLL gene carry a poor prognosis. Over the past 6 years, it has become increasingly clear that fusions of MLL induce widespread epigenetic deregulation that may mediate much of their transforming activity. The histone methyltransferase DOT1L, which methylates histone 3 on lysine 79 (H3K79), has received particular attention. Genome-wide H3K79 methylation profiles in MLL-rearranged leukemias are abnormal, and can serve to distinguish MLL-rearranged from other types of leukemias. Loss of H3K79 methylation affects expression of MLL-target loci and is detrimental to the leukemogenic activity of MLL-rearranged cells, suggesting that a DOT1L dependent, aberrant epigenetic program drives transformation in these leukemias. Small molecule DOT1L inhibitors have been developed and selectively inhibit proliferation of MLL-rearranged leukemia cells. These molecules are now in clinical trials for patients with relapsed refractory leukemia. Also, the Polycomb Repressive Complex 2 (PRC2) has been implicated in self-renewal and cancer progression, and its components are overexpressed in many cancers, but its role in cancer development and progression remains unclear. We have used conditional alleles for the PRC2 components Enhancer of Zeste 2 (Ezh2) and Embryonic Ectoderm Development (Eed) to characterize the role of PRC2 function in leukemia development and progression. Compared to wildtype leukemia, Ezh2-null MLL-AF9-mediated acute myeloid leukemia (AML) show decreased organ infiltration and failed to accelerate upon secondary transplantation. However, Ezh2-null leukemias maintained self-renewal up to the third round of transplantation, indicating that Ezh2 is not strictly required for MLL-AF9 AML. In contrast, inactivation of the essential PRC2 gene, Eed led to complete ablation of PRC2-function, which is incompatible with leukemia growth. Gene expression array analyses indicated more profound gene expression changes in Eed-null compared to Ezh2-null leukemic cells, including downregulation of Myc target genes and upregulation of PRC2 targets. These data show that histone-modifying enzymes play critical roles in leukemia and may be relevant therapeutic targets in these diseases.
Citation Format: Scott A. Armstrong. Targeting histone methylation in leukemia. [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 IA08.
Abstract IA15: Epigenetics of hormone dependence
Authors: Brown Myles 
Published: August 2014

Abstract
A detailed understanding of interplay between genetics and epigenetics in the progression and hormone dependence of distinct cancer subtypes is critical to the development of new approaches to prevention and therapy. Steroid hormones and their receptors play essential roles in the development and progression of both breast and prostate cancers. It remains unknown what role an epigenetically defined cell of origin plays in determining hormone responsiveness. In addition whether acquired resistance to endocrine therapy is the result of clonal evolution or the presence of hormone independent tumor-initiating cells, or both remains to be determined. Gain of function mutations and gene amplification of the androgen receptor (AR) in prostate cancer and the estrogen receptor (ER) in breast cancer in a subset of hormone refractory cases supports clonal evolution as the dominant mechanism of resistance in in these patients. We have investigated how the pathways downstream of AR and ER are activated in cases where they are not genetically altered and whether these depend on mutations in other epigenetic regulators including other transcription factors involved in steroid receptor networks and chromatin modifying enzymes involved in transcriptional regulation mediated by these receptors. Renewed success in targeting the steroid receptors themselves and promising advances in inhibiting the activity of the chromatin modifying enzymes provides new opportunities for the treatment of patients with breast and prostate cancer.
Citation Format: Myles Brown. Epigenetics of hormone dependence. [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 IA15.
Abstract IA17: The stem cell factor LIN28 in pediatric cancer
Authors: Daley George Q. 
Published: August 2014

Abstract
LIN28, a developmental regulator originally identified as a heterochronic mutant in C. elegans, functions as an RNA binding protein that regulates protein expression through effects on mRNA translation and through control of processing of the let-7 family of tumor suppressor microRNAs. Lin28 has two paralogs, Lin28A and Lin28B, and studies have revealed a role for these factors in a wide array of biological phenotypes including organismal growth and metabolism, sexual maturation, and oncogenesis. LIN28/let-7 act antagonistically to regulate the balance of self-renewal and differentiation in embryonic stem cells, and LIN28 is one of the factors shown to reprogram somatic cells to pluripotency. In pediatric cancers, high level expression of LIN28 is a consistent marker of germ cell tumor, frequently observed in neuroblastoma and hepatoblastoma, and activated by chromosomal translocation in Wilms tumor. Thus, the stem cell factor LIN28 is commonly dysregulated in pediatric tumors and may represent a novel therapeutic target.
Citation Format: George Q. Daley. The stem cell factor LIN28 in pediatric 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 IA17.
Abstract IA20: Epigenetic deregulation of gene expression
Authors: Melnick Ari 
Published: August 2014

Abstract
Epigenetic deregulation of gene expression through aberrant DNA methylation or histone modification plays an important role in the malignant transformation of hematopoietic cells. In particular, acute myeloid leukemias (AMLs) can be classified according to epigenetic signatures affecting DNA methylation or histone modifications affecting specific gene sets. Heterozygous somatic mutations in the loci encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in ~20% of AMLs and are accompanied by global DNA hypermethylation and hypermethylation and silencing of a number of specific gene promoters. IDH1/2 mutations are almost completely mutually exclusive with somatic loss of function mutations in TET2, which hydroxylates methylcytosine (mCpG). DNA hydroxymethylation can function as an intermediate step in mCPG demethylation. TET2 mutant de novo AMLs also display global and promoter specific hypermethylation partially overlapping with IDH1/2 mutant cases. Mutations in the IDH1/2 loci result in a neomorphic enzyme that generates the aberrant oncometabolite 2-hydroxyglutarate (2HG) using alpha-ketoglutarate (aKG) as a substrate. 2HG can disrupt the activity of enzymes that use aKG as a cofactor, including TET2 and the Jumonji family of histone demethylases. Expression of mutant IDH isoforms inhibit TET2 hydroxymethylation and Jumonji histone demethylase functions. IDH and TET2 mutant AMLs accordingly exhibit reduced levels of hydroxymethylcytosine and a trend towards reduced histone methylation. Mutant IDH or TET2 loss of function causes differentiation blockade and expansion of hematopoietic stem cells and TET2 knockout results in a myeloproliferative phenotype in mice. Hydroxymethylcytosine is abundance in hematopoietic stem cells, and displays specific distribution patterns, and yet the function of this covalent modification is not fully understood. Recent data link TET2 with the function of cytosine deaminases as a pathway towards DNA demethylation, which has implications as well for B-cell lymphomas and CML lymphoid blast crisis, which are linked with the actions of activation induced cytosine deaminase. Altogether, the available data implicate mutations in IDH1/2 and TET2 in promoting malignant transformation in several tissues, by disrupting epigenomics programming and altering gene expression patterning.
Citation Format: Ari Melnick. Epigenetic deregulation of gene expression. [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 IA20.