bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2082: Deciphering the nucleosome acidic patch binding at amino acid resolution
Authors: Skrajna Aleksandra , Simmons Holly , Smith Charlotte , Mcpherson Jeanne-Marie E. , Goldfarb Dennis , McGinty Robert K. 
Published: July 2021

Abstract
In all eukaryotic cells, nucleosomes provide basic organization of genomic DNA and serve as signaling hubs for gene expression, DNA replication and DNA damage repair. These genome-templated processes are tuned by chromatin enzymes that introduce chemical modifications to nucleosomes and control their positioning and occupancy. Mutations in genes encoding chromatin enzymes are highly correlated with numerous cancer types. A thorough exploration of how these chromatin enzymes act on their physiologic target, the nucleosome, is critical to understanding abnormal DNA methylation, histone posttranslational modifications, and chromatin composition, leading to cancer. In our recent nucleosome interactome proteomic screen, we demonstrated that the vast majority of nuclear proteins require a group of acidic residues on the nucleosome disk surface to interact with nucleosomes. This acidic patch and an adjacent region were recognized by over 50% and 18% of nuclear proteins, respectively, while almost half of the nucleosome disk surface contributed only minimally to nucleosome recognition. Overall, we paired about 300 proteins representing diverse nuclear functions including DNA methylation (DNMT1 and 3, Tet1), histone modification (HAT complexes, kinases), nucleosome remodeling (SWI/SNF), DNA repair (MRN complex), DNA replication (ORC complex), RNA processing, and cell cycle progression (APC/C) with specific nucleosome surface requirements. We have now repeated our screen at amino acid resolution using a library of fifteen nucleosomes containing single point mutations in and around the acid patch, including potential histone oncomutations identified to be overrepresented in cancers. Using our nucleosome library, we preformed pulldowns from human embryonic kidney 293 cell nuclear lysates to comprehensively evaluate the role of single histone residues in nucleosome recognition. Overall, this study dissects the primary nucleosome binding hot-spot at high resolution and provide a robust resource for further exploration of the nucleosome interactome in normal and cancer cell biology.
Citation Format: Aleksandra Skrajna, Holly Simmons, Charlotte Smith, Jeanne-Marie E. Mcpherson, Dennis Goldfarb, Robert K. McGinty. Deciphering the nucleosome acidic patch binding at amino acid resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2082.
Abstract 2086: Differential immune-cell landscape in tissue and liquid biopsy specimens is associated with recurrence risk across meningioma methylation-subtypes
Authors: Herrgott Grayson A. 
Published: July 2021

Abstract
Background. Tumor-infiltrating immune cells can favor or inhibit tumor growth, constituting promising and alternative targets for treatment of patients with meningiomas (MNG), a prevalent primary intracranial tumor with no known therapy beyond surgery and radiation. Immune-cell composition can predict therapy response in other diseases, therefore, profiling immune-cell infiltrates in these tumors is crucial, preferentially by non-invasive approaches. Genome-wide methylation arrays are powerful tools to classify and assess cell composition either in tumor tissue or with liquid biopsy.
Objective: We aim to apply methylation-based classifiers to estimate immune-cell composition of tumor tissue and serum specimens to predict recurrence-free survival in patients with MNG.
Methods: We conducted unsupervised and supervised analyses of the methylome of a multicenter MNG cohort composed of 326 tissue, 60 serum and 9 control specimens. Immune-cell composition (B-cells, CD4-T & CD8-T cells, neutrophils, natural killer cells, and monocytes) and recurrence risk were estimated using methylation-based classifiers. We used the point-biserial correlation method to analyze associations across categorical clinical and molecular features.
Results: We identified four distinct methylation subgroups of MNG (in serum or tissue) that presented a differential immune cell landscape composition. In the tissue, MNG methylation subgroups were mutually exclusive in enrichment or depletion of NK-, cytotoxic T- or monocyte-cell methylation signatures and in the serum, they were enriched of monocyte- and B-cell signatures. Distinct Immune-cell signatures (Monocytes, CD8T and Neutrophils) were correlated with risk of recurrence or grade in MNG tissue and/or liquid biopsy specimens.
Conclusion: DNA methylation-based deconvolution allowed for the detection of differential immune-cell composition across MNG methylation-subtypes in tissue that could be detected in liquid biopsy specimens. Distinct immune-cell signatures correlated with MNG recurrence risk/grade (e.g. T-cell) in our cohort were reported to improve anti-tumoral immune response in many tumors. These results suggest that profiling tumor immune-cell landscape can inform tumor behavior and provide insight in application of existing and novel therapeutic approaches in MNG.
Citation Format: Grayson A. Herrgott. Differential immune-cell landscape in tissue and liquid biopsy specimens is associated with recurrence risk across meningioma methylation-subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2086.
Abstract 2087: Breast tissue-specific DNA methylation levels predicted by genetic variants in association with breast cancer
Authors: He Chunyan , Castle James , Lin Nan , Liu Jinpeng , Wang Chi , Liu Yunlong 
Published: July 2021

Abstract
Aberrant DNA methylation (DNAm) contributes to the development of breast cancer. Both genetic and environmental factors influence DNAm levels in a tissue-specific fashion. Previously studies have reported that genetically predicted DNAm levels at CpGs were associated with breast cancer risk. However, the prediction models were built based on DNAm measured in blood, which may not be the most relevant tissue for breast cancer. In this study, we aim to build statistical models to predict breast tissue-specific DNAm levels using genetic data and DNAm sequencing data of normal breast tissue from healthy women (N=293). We applied these models to the GWAS data from the Breast Cancer Association Consortium that includes 46,785 breast cancer patients and 42,892 controls. We evaluated the association of genetically predicted breast tissue-specific DNAm levels at CpGs with breast cancer risk using MetaXcan. Due to our small sample size of normal breast tissue samples, we restricted our statistical models to those that were well-validated and highly correlated between predicted and measured DNAm levels (r≥0.6). We thus identified 45 CpGs that were significantly associated with breast cancer risk after correction for multiple testings, and many of these CpGs were also differentially methylation between breast tumor and normal tissue samples. Genes annotated to these CpG sites are enriched in Wnt signaling, cell cycle, and stem cell proliferation pathways, including known genes such as FGFR2, KLF4, CASC8, TERT, and EMBP1. We also identified novel putative DNAm markers for the development of breast cancer. Our study provides insight into tissue-specific genetic regulation of DNAm in normal breast tissue.
Citation Format: Chunyan He, James Castle, Nan Lin, Jinpeng Liu, Chi Wang, Yunlong Liu. Breast tissue-specific DNA methylation levels predicted by genetic variants in association with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2087.
Abstract 2088: The effect of sorghum on epigenetic modifications in colon cancer
Authors: Kamagate Zeguela , Smolensky Dmitriy , Tsuji Petra 
Published: July 2021

Abstract
Colorectal cancer is a major public health issue, accounting for nearly 150,000 cases annually. Because colorectal cancer is correlated with inflammation and oxidative cellular stress, it would be highly beneficial to exploit bioactive components in our diet that could potentially inhibit cancer promotion. Certain varieties of the dietary grain sorghum (S. bicolor) contain high amounts bioactive polyphenols, which may contribute to the prevention of colon cancer due to their antioxidant properties, anti-inflammatory, and anti-carcinogenesis effects, some of which may be mediated by epigenetic mechanisms. Tumor suppressor genes are often hyper-methylated in tumors. Therefore, DNA methylation and histone acetylation patterns may affect the expression of genes that play a role in the promotion or prevention of colon cancer. Our objective is to investigate how high-polyphenol sorghum varietals impact epigenetic mechanisms in human colon cancer cells, including quantitating global DNA methylation and histone acetylation. We treated HCT116 human colon cancer cells with high-polyphenol sorghum extracts or solvent control, or 5 µM epigallocatechin gallate as a positive control, as it's known to decrease DNA methylation. Total RNA, protein, and DNA were harvested after 24 and 48 hours. mRNA expression of DNA methyltransferases (DNMT) were quantitated with qPCR. Our preliminary results suggest that high polyphenol sorghum may decrease the mRNA expression of DNMT1, the key enzyme that upholds methylation patterns after DNA synthesis. Furthermore, mRNA expression of DNMT 3A, which is the enzyme responsible for de novo DNA methylation, also indicated a decrease. We further plan to assess protein expression and catalytic activity of DNMTs and histone acetyltransferases in addition to global DNA methylation and histone acetylation to investigate the impact of these high polyphenol sorghum varietals on relevant epigenetic mechanisms in both HCT116 and CACO-2 cells. Consumption of high-polyphenol sorghum as part of the human diet may lead to global or gene-specific hypo-methylation or hyper-acetylation, and this may be of importance in the prevention of colon cancer. Research supported by USDA ARS Kansas.
Citation Format: Zeguela Kamagate, Dmitriy Smolensky, Petra Tsuji. The effect of sorghum on epigenetic modifications in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2088.
Abstract 2116: Promoter enrichment of subnucleosomes using breast cancer cell-free DNA
Authors: Zukowski Alexis , Han Amy , Kabos Peter , Ramachandran Srinivas 
Published: July 2021

Abstract
Breast cancer is the leading cancer diagnosis and the second major cause of cancer-related deaths in women worldwide. The use of non-invasive cell-free DNA (cfDNA) to detect and assess cancer dynamics has recently gained traction with a focus on targeted mutation panels. However, mutation panels have to contend with non-tumor origin of mutations like clonal hematopoiesis and the emergence of novel mutations in the tumor. A potential alternative is to harness the epigenomic, or non-genetic, features of cfDNA. In a healthy individual, blood cell turnover is the major contributor to the cfDNA pool. In cancer, tumor DNA adds to the cfDNA pool, which represents the end product of endogenous nucleases acting on accessible genomic DNA. Since genomic DNA is protected by histone proteins, cfDNA maps the chromatin structure of individual cells that turn over. Subnucleosomes (partially formed structures of nucleosomes that are the building blocks of chromatin) are by-products of transcription and thus reflect small protections enriched in active genes. The enrichment of subnucleosomes at promoters correlate with gene expression profiles of cfDNA tissues-of-origin and based on this knowledge, we hypothesized that we could reconstruct the transcriptional profiles of cancer cells by selectively targeting promoter regions. We first extracted cfDNA from 9 healthy female donors and 8 patient donors with various stages of breast cancer (Stage I, n=1; Stage III, n=1; Stage IV, n=4). We used a single-stranded DNA library protocol that robustly captures highly nicked cfDNA, enabling the genome-wide mapping of both nucleosomes and subnucleosomes. We performed targeted capture of promoter-proximal, nucleosome-protected sequences in cfDNA using non-overlapping tiling probes from transcription start sites to 300 bp downstream. After whole-genome sequencing of pooled libraries, we show that 76.4% (n=13/17) of samples exhibited &gt;10X enrichment compared to unenriched samples, and 64.7% (n=11/17) of samples exhibited &gt;100X enrichment. The enriched samples allowed us to profile &gt;10,000 genes, whereas unenriched samples enabled profiling between 100-10,000 genes at an average sequencing depth of 40 million reads. Overall, we obtain higher depth per sequencing read after enrichment resulting in a high-resolution snapshot of promoter-nucleosome dynamics derived by probing only ~0.18% of the genome. We believe that this significant advancement will allow us not only to identify presence of cancer but also detect distinct tumor states.
Citation Format: Alexis Zukowski, Amy Han, Peter Kabos, Srinivas Ramachandran. Promoter enrichment of subnucleosomes using breast cancer cell-free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2116.
Abstract 2119: Genome-wide epigenetic alterations in T-cell prolymphocytic leukemia
Authors: Tian Shulan , Zhang Henan , Klee Eric , Yan Huihuang , Ding Wei 
Published: July 2021

Abstract
T-cell prolymphocytic leukemia (T-PLL) is a rare disease showing a rapid clinical course, with a median survival of &lt;1 year. Whole-genome and whole-exome sequencing have identified key genetic lesions in T-PLL, including structural alterations such as inversions, translocations, and large copy number variants, as well as recurrent somatic mutations of genes encoding chromatin regulators and of those in the JAK-STAT signaling pathway. Epigenetic alteration is implicated in the susceptibility and progression of both cancer and non-cancerous diseases. However, genome-wide epigenetic data has not been generated for T-PLL, which prohibits the mechanistic studies of transcriptional misregulation in T-PLL. This study used micrococcal nuclease digestion and sequencing (MNase-seq) to profile the chromatin accessible regions, i.e., gene regulatory regions such as promoters, enhancers and insulators, in both T-PLL patients and healthy individuals. Our analysis revealed the prevalence of lost open chromatin regions in T-PLL. We also generated histone H3 lysine 4 monomethylation (H3K4me1) and lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation and sequencing (ChIP-seq) data from the same samples. We identified 5,462 and 2,833 active enhancers (&gt;=2.5 kb away from transcription start sites) that are lost and gained in T-PLL, respectively, compared to normal. The differential H3K27ac peaks are preferentially associated with the nearest genes differentially expressed between T-PLL and normal (chi-square test p &lt;2.2e-16), indicating a role of epigenetic alteration in transcriptional misregulation. In addition, we identified alterations of active enhancers that target oncogenes with key roles in T-PLL, such as TCL1Aand MYC. Together, our analysis has provided insights into the epigenetic mechanisms that drive oncogenic activation in T-PLL.
Citation Format: Shulan Tian, Henan Zhang, Eric Klee, Huihuang Yan, Wei Ding. Genome-wide epigenetic alterations in T-cell prolymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2119.
Abstract 2125: Roles of KAT6A and KAT6B in the biology of estrogen positive breast cancer
Authors: Meaux Isabelle , Gorge-Bernat Dimitri , Paz Angele , Geslin Catherine , Debussche Laurent , Moll Jürgen , Henry Christophe 
Published: July 2021

Abstract
KAT6A and KAT6B are histone acetyl transferase (HAT) that are controlling gene expression by transferring acetyl groups to histones. Yu et al (Oncogene, 2017 36, 2910-2918) have shown that KAT6A has a role in breast cancer development by activating the ERα promoter and was found frequently amplified in 11% and is overexpressed in 15% of breast cancers. Altogether, these data support KAT6A as an attractive target in estrogen receptor driven breast cancer. KAT6B is a close homolog that shares 91% identity in the acetyl coA binding site. While the prevalence of gene amplification for KAT6B in breast cancer is only 1-2%, it is often overexpressed. In this study, we are exploring how KAT6A and KAT6B are contributing to ERα expression and the growth of KAT6A amplified breast cancer cell lines. To decipher each protein's role, we have designed specific siRNA against KAT6A and KAT6B and we tested their action either individually or in combination in the KAT6A gene amplified breast cancer cell lines T-47D, CAM-1 and ZR-75. Following treatment of T-47D, CAMA-1 and ZR75 cell lines with KAT6A or B siRNA we observed a decrease of ERα gene and protein expression for all siRNAs. The effect was more pronounced when using KAT6A over KAT6B and the effect of both siRNA A/B were additive. Phenotypically, the impact on cell line proliferation by applying clonogenic and incucyte assays, mirrors what is observed on ERα gene and protein expression. The effect on cellular proliferation of KAT6A is more prominent than KAT6B silencing, while the combined KAT6A + KAT6B silencing being more impactful than KAT6A silencing alone. In conclusion, our data show that KAT6A and KAT6B share similar function in the control of ER gene and protein expression. This study suggests that KAT6A and KAT6B may be paralogs, one compensating for the loss of the other. This translates into a more pronounced antiproliferative effect when both genes are silenced concomitantly.
Citation Format: Isabelle Meaux, Dimitri Gorge-Bernat, Angele Paz, Catherine Geslin, Laurent Debussche, Jürgen Moll, Christophe Henry. Roles of KAT6A and KAT6B in the biology of estrogen positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2125.
Abstract 2129: Usp22 controls multiple signaling pathways in development and disease
Authors: Koutelou Evangelia , Kuang Xianghong , Dent Sharon Y. 
Published: July 2021

Abstract
Our research is focused on defining the functions of histone-modifying enzymes in normal cells so that we can understand how alterations in these activities contribute to tumor development or progression. The highly conserved SAGA complex plays important roles at multiple steps of gene transcription in yeast, flies, and mammalian cells. This modular complex houses two enzymatic activities, the GCN5 histone acetyltransferase, and the USP22 deubiquitinase. USP22 is overexpressed in highly aggressive, therapy-resistant cancers, but the normal functions of this deubiquitinase are not well defined. Our detailed analysis of the embryonic lethality observed in the Usp22-/- mouse model we generated highlighted a critical role for Usp22 in the developing placenta. We found that Usp22 deletion in mice results in embryonic lethality due to defects in the formation and organization of extra-embryonic placental tissues, culminating in failure to establish proper vascular interactions with the maternal circulatory system. These phenotypes arise from abnormal gene expression patterns that reflect defective kinase signaling, including TGFß and several receptor tyrosine kinase (RTK) pathways. Interestingly, overexpression of USP22 in mice leads to an over branching phenotype of the mammary gland, which is linked to the deregulation of the signaling pathways described above. Our results provide insights to potential angiogenic functions of the SAGA complex, indicate that Usp22 is critical for the proper execution of multiple signaling pathways important for normal development, and provide new clues towards Usp22 contributions to cancer and other disease states.
Citation Format: Evangelia Koutelou, Xianghong Kuang, Sharon Y. Dent. Usp22 controls multiple signaling pathways in development and disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2129.
Abstract 213: BART cancer: A web resource for transcriptional regulators in cancer genomes
Authors: Thomas Zachary V. , Wang Zhenjia , Zang Chongzhi 
Published: July 2021

Abstract
The goal of this study is to develop a comprehensive data resource for transcriptional regulator activities in various cancers. Dysregulation of gene expression plays an important role in cancer development. Identifying transcriptional regulators (TRs), including transcription factors and chromatin regulators, that drive the oncogenic gene expression program is a critical task in cancer research. Genomic TR profiling data from primary cancer samples are limited in the public domain. Here, we present BART Cancer, an interactive web resource database to display putative TRs that are responsible for regulating differentially expressed genes across 15 different cancer types included in The Cancer Genome Atlas (TCGA). BART Cancer integrates over 10,000 gene expression profiling RNA-seq datasets from TCGA with over 7,000 ChIP-seq datasets from the Cistrome Data Browser database and the Gene Expression Omnibus (GEO). BART Cancer uses Binding Analysis for Regulation of Transcription (BART) for predicting TRs from differentially expressed genes comparing cancer samples with normal samples for each cancer type. BART Cancer also displays the activities of over 900 TRs across cancer types, by integrating computational prediction results from BART and from the Cistrome Cancer database. Focusing on transcriptiona regulatory activities in human cancers, BART Cancer provides unique insights into epigenetics and transcriptional regulation in cancer, and is a useful data resource for genomics and cancer research communities. BART Cancer web resource can be accessed at: http://bartcancer.org.
Citation Format: Zachary V. Thomas, Zhenjia Wang, Chongzhi Zang. BART cancer: A web resource for transcriptional regulators in cancer genomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 213.