bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A023: Sensitivity/resistance mechanisms to KDM5 inhibition in basal breast cancer
Authors: DiCiaccio Benedetto , Papachristou Evangelia , Papanastasiou Malvina , Reiter Andrew , Carroll Jason , Polyak Kornelia 
Published: December 2022

Abstract
We previously described that the KDM5B histone H3 lysine 4 demethylase is amplified and overexpressed in luminal estrogen receptor positive breast cancer, and its activity is associated with resistance to endocrine therapies. We have found that the KDM5A paralog is specifically amplified and overexpressed in basal breast cancer, providing a novel therapeutic opportunity for an aggressive breast cancer subtype. To identify modulators of KDM5 inhibitor sensitivity in KDM5A-amplified basal breast cancer, we performed a genome wide CRISPR viability screen in a KDM5A-amplified basal breast cancer cell line. Our CRISPR screen results and follow up studies implicate Rho-GTPase signaling and the transcriptional repressor ZBTB7A as modulators of cellular response to KDM5 inhibition. We are currently investigating the underlying mechanisms for how these components alter sensitivity/resistance to KDM5 inhibition. Our results suggest potential therapeutic opportunities of inhibiting the KDM5 family of H3K4 demethylases in basal breast cancer.
Citation Format: Benedetto DiCiaccio, Evangelia Papachristou, Malvina Papanastasiou, Andrew Reiter, Jason Carroll, Kornelia Polyak. Sensitivity/resistance mechanisms to KDM5 inhibition in basal breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A023.
Abstract A026: Epigenetic factor competition reshapes the EMT landscape
Authors: Al-Radhawi M. Ali , Tripath Shubham , Zhang Yun , Sontag Eduardo , Levine Herbert 
Published: December 2022

Abstract
The emergence of and transitions between distinct phenotypes in isogenic cells can be attributed to the intricate interplay of epigenetic marks, external signals, and gene regulatory elements. These elements include chromatin remodelers, histone modifiers, transcription factors, and regulatory RNAs. Mathematical models known as Gene Regulatory Networks (GRNs) are an increasingly important tool to unravel the workings of such complex networks. In such models, epigenetic factors are usually proposed to act on the chromatin regions directly involved in the expression of relevant genes. However, it has been well-established that these factors operate globally and compete with each other for targets genome-wide. Therefore, a perturbation of the activity of a regulator can redistribute epigenetic marks across the genome and modulate the levels of competing regulators. These interactions have been brought to the fore by recent experiments (Zhang, Donaher et al, 2022) reporting that the knockouts of different histone methyltransferases can induce two distinct trajectories of EMT, characterized by distinct and unexpected changes in gene expression profiles. In this work, we propose a new modeling framework that combines local transcriptional regulation with global epigenetic control, and show that complex interplay between transcriptional and epigenetic control can lead to rich gene expression dynamics. We use our modeling framework to understand the effects of various epigenetic perturbations on the epithelial-mesenchymal transition, a crucial cellular process involved in both health and disease. We note that the interplay between epigenetic competition, the EMT transcriptional network, and the baseline transcriptional context can result in counter-intuitive experimental observations, and generate unique paths for cells to transition between epithelial and mesenchymal states. We apply our modeling framework to explain the aforementioned recent experimental findings (Zhang, Donaher et al, 2022), and we use it to offer verifiable predictions. One crucial takeaway from our modeling is that experiments involving epigenetic perturbations must be analyzed with care due to the possibility of widespread cross-talk between the genomic targets of different epigenetic factors. This means that the biological consequence of perturbation to an epigenetic modifier could be an outcome of changes in the expression levels of its direct genomic targets or simply a side-effect from the dilution and distribution of an entirely different epigenetic modifier.
Citation Format: M. Ali Al-Radhawi, Shubham Tripath, Yun Zhang, Eduardo Sontag, Herbert Levine. Epigenetic factor competition reshapes the EMT landscape. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A026.
Abstract A028: Investigating the epigenetic landscape of chemotherapy-induced polyaneuploid prostate cancer cells
Authors: Gonye Anna , Kim Chi-Ju , Pienta Ken , Amend Sarah 
Published: December 2022

Abstract
While localized prostate cancer (PCa) has a high treatment success rate, over 30,000 individuals in the United States and 350,000 men globally die each year from therapy resistant, metastatic PCa. A thorough understanding of the factors contributing to PCa recurrence following development of therapy resistance is acutely needed in order to develop efficacious treatments and disease-management strategies. Our group and others have identified a unique minority population of physically enlarged cancer cells with polyaneuploid genomes, termed polyaneuploid cancer cells (PACCs), in the tumors of patients with metastatic prostate cancer and in other tumor types. PACCs are the result of a polyaneuploid transition that occurs when aneuploid cancer cells experience environmental or therapeutic stress. These aneuploid cancer cells then pause their cell cycle after whole genome doubling to survive the environmental insult. Cancer cells in the PACC state appear to be quiescent and have an increased capacity for invasion/motility, an ability to endure in stressful or novel environments, and a propensity to undergo depolyploidization to re-establish the cancer cell population. We hypothesize that PACCs are critical players in prostate cancer therapy resistance and recurrence. We seek to better understand the life cycle of the PACC state in PCa in order to inform the design of new therapeutic strategies that prevent disease recurrence. Our data suggests that PCa cells in the PACC state tend to have a large polyploid single nucleus more frequently than multiple smaller, single nuclei, though both are observed at all timepoints in PACC recovery. Nuclear morphology and size certainly will impact the way that a cell organizes and utilizes its genome. Additionally, genome organization and stability have been demonstrated to be important factors/drivers of cancer development, progression, and recurrence. Importantly, epigenetic changes such as histone modifications can drastically affect chromatin condensation, which subsequently can alter the gene accessibility and transcription profile of a cell. We hypothesize that cancer cells in the PACC state have different histone modifications and different regions of accessible chromatin compared to parental cancer cells, and that these differences will also impact the gene expression of PACCs.
Citation Format: Anna Gonye, Chi-Ju Kim, Ken Pienta, Sarah Amend. Investigating the epigenetic landscape of chemotherapy-induced polyaneuploid prostate cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A028.
Abstract B001: Chromatin engineering using a dCas9-based inducible dimerization system
Authors: Bergwell Mary , Park JinYoung , Pistoni Laura , Kirkland Jacob G. 
Published: December 2022

Abstract
Epigenetic cancers lead to tumor progression via oncogene activation, tumor suppressor silencing, cell fate transitions, and genomic instability. Approximately 50% of tumors have alterations in Chromatin regulators. One group of Chromatin regulators, the mSWI/SNF complexes, are mutated in 20% of tumors making them one of the most mutated chromatin regulator complexes in cancer. In the past, the mechanism of action of ATP-dependent chromatin regulators, such as mSWI/SNF was largely explored using in vitro methods based on measurements of nucleosome mobility. These studies were limited by the fact that these assays were not sensitive to tissue-specific chromatin modifications, topology, long-range interactions, and complex patterns of histone modifications as well as patterns of DNA methylation and human disease mutational backgrounds. To circumvent these problems, we developed the FIRE-Cas9 system that allows one to recruit a specific chromatin regulator and follow the consequences with minute-by-minute kinetics on physiologic chromatin. I can examine any locus of biological or medical importance in virtually any cell type using this technique. We can recruit endogenous proteins or protein complexes such as different mSWI/SNF complexes, histone methyltransferases, or histone demethylases and assay changes in chromatin state and transcriptional state. Because chromatin regulator complexes have alterations in many human cancers, it is imperative to understand the mechanism of action of these complexes with unparalleled precision as a basis for therapeutic development. The FIRE-Cas9 system allows one to do this for the first time.
Citation Format: Mary Bergwell, JinYoung Park, Laura Pistoni, Jacob G. Kirkland. Chromatin engineering using a dCas9-based inducible dimerization system. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B001.
Abstract B004: Analysis of epigenetic marks and mechanisms in disease: Your guide to a successful assay
Authors: Comeau Christopher C. , Guo Angela H. , Chen Fang , Fry Christopher J. 
Published: December 2022

Abstract
Like the chromatin immunoprecipitation (ChIP) assay, Cleavage Under Targets & Release Using Nuclease is a powerful and versatile technique used for probing protein-DNA interactions within the natural chromatin context of the cell. The assay can be combined with downstream qPCR or NG-seq to analyze histone modifications and binding of transcription factors, DNA replication factors, or DNA repair proteins at specific target genes or across the entire genome. It provides a rapid, robust, and true low cell number assay for detection of protein-DNA interactions in the cell. Unlike the ChIP assay, it is free from formaldehyde cross-linking, chromatin fragmentation, and immunoprecipitation. Previously, we have shown that, compared to ChIP, it requires fewer starting cells (100K), has a much faster protocol (one day from cells to DNA), generates lower background signal (requires less sequencing depth), and offers spike-in control DNA for effective normalization of signal between samples and between experiments. We recently updated the CST Assay Kit for use with 5,000-20,000 cells and added protocols for fixed cells and tissue. I will discuss the basics of the assay and important factors to consider when setting up your experiment. In addition, I will provide data showing the versatility of this assay for mapping various histone modifications, transcription factor, and transcription cofactor binding across multiple sample types. Finally, I will discuss how the general protocol is optimized for greater signal to noise ratio, reduced number of starting cells, and provide an alternative digestion method to prepare the input DNA as a critical control of the experiment.
Citation Format: Christopher C. Comeau, Angela H. Guo, Fang Chen, Christopher J. Fry. Analysis of epigenetic marks and mechanisms in disease: Your guide to a successful assay. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B004.
Abstract B016: A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons
Authors: Starble Rebecca M. , Sun Eric G. , Jensen Tyler B. , Gbyli Rana , Sun Ning , Xiao Andrew Z. 
Published: December 2022

Abstract
Lung cancer is the leading cause of cancer-related death worldwide and affects over 2 million people each year. In lung adenocarcinoma (LUAD), somatic activating mutations of epidermal growth factor receptor (EGFR) occur in approximately 15% of patients. The first-line therapy for patients with EGFR-mutant LUAD is administration of osimertinib, an EGFR tyrosine kinase inhibitor (TKI). While many patients’ tumors initially respond to osimertinib treatment, resistance inevitably develops in most cases, which is a major challenge that hinders treatment efficacy. One common mechanism of resistance to osimertinib is the amplification of oncogenes, such as MET, HER2, and RET. Despite the high prevalence of oncogene amplifications in resistant tumors, the mechanisms that control oncogene amplification and transcription are poorly understood. Recent work has shown that oncogenes are frequently amplified on extrachromosomal DNA (ecDNA), which are circularized and highly amplified DNA sequences that are present in at least 14% of human cancers. Additional studies have implicated ecDNA amplification in the acquisition of resistance to TKIs, yet the mechanisms through which ecDNA is regulated are largely unknown. In the present study, we have identified a novel epigenetic factor that promotes the acquisition of TKI resistance through the organization and transcription of oncogene amplicons, some of which occur on ecDNA. To determine whether this factor binds to DNA, we used and found that it is enriched at the promoters of amplified oncogenes. Further, we performed protein immunoprecipitation followed by mass spectrometry and identified multiple candidate interacting factors, such as histone readers and components of the cohesin machinery. Depletion of this epigenetic factor prevents the acquisition of TKI resistance and leads to reduced transcription of oncogene amplicons. Thus, we propose a novel mechanism that promotes the acquisition of TKI resistance via the spatial organization and transcription of oncogene amplicons.
Citation Format: Rebecca M. Starble, Eric G. Sun, Tyler B. Jensen, Rana Gbyli, Ning Sun, Andrew Z. Xiao. A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B016.
Abstract B017: Dysregulation of ultra long-range DNA methylation canyon interactions in human acute myeloid leukemia
Authors: Wang Xue Qing D. , Feng Fan , Dou Yali , Liu Jie , Zhang Xiaotian 
Published: December 2022

Abstract
DNA methylation Canyons (DMCs) are genomic regions devoid of DNA methylation over 3.5kb in hematopoietic stem cells (HSCs). DMCs form ultra long-range interactions spanning decades of megabases specifically in HSCs. These ultra-long DMC interactions between DMCs relies on the strong Polycomb binding inside DMC regions. DMCs are hypermethylated and partially activated in cancer. However, its 3D genomic alterations have not been examined extensively. Here we profiled the high-resolution 3D genomic interactions in 7 primary human acute myeloid leukemia (AMLs). Focusing on DMCs' epigenome state, we found that DMCs in all AMLs are hypermethylated and lose the strong Polycomb enrichment within DMCs in comparison with HSC. Based on the DMC interactions, we discovered two subtypes of AMLs with distinct 3D genomic dysregulation of DMCs’ long-range interactions. In the first AML subtype, DMCs’ interactions are still strong as HSPC but gained leukemia-specific long-range interactions. This subtype is enriched for WT1 mutations and is characterized by the expression of CD34 on blast cells. This particular subtype displayed a global basal level increase in the H3K27me3 mark in the genome. This particular subtype of AML is also sensitive to the EZH2 inhibitor treatment. The EZH2 inhibitor treatment leads to the differentiation of blasts and reduces the colony-forming ability of this subtype of AML. Further dissection shows the EZH2 inhibitors could eradicate the leukemia-specific ultra-long range interactions. In the second subtype of AML, 3D genomic interactions between DMCs significantly lost in AMLs with high HOX cluster gene expression (MLL-r and NPM1c+ AMLs). We further found repressive DMC genes, which are developmental transcriptional factors(TFs) in organ formation are activated in these AMLs. Interestingly, these developmental TFs are involved in forming leukemia-specific long-range interactions independent of CTCF-mediated TADs and chromosomal loops. Among those TFs, IRX3 and IRX5 are frequently activated in MLL-r, NPM1c+ AML and MPAL. These two genes have also been shown before to immortalize bone marrow progenitor cells and block differentiation of these progenitor cells. The loci of these two genes form strong long-range connections to an upstream FTO enhancer mimicking the 3D genomic structure observed in developing muscle and brains.
Citation Format: Xue Qing D. Wang, Fan Feng, Yali Dou, Jie Liu, Xiaotian Zhang. Dysregulation of ultra long-range DNA methylation canyon interactions in human acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B017.
Abstract B026: Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets
Authors: Tang Fanying , Xu Duo , Wang Shangqian , Wong Chen Khuan , Martinez-Fundichely Alexander , Lee Cindy , Cohen Sandra , Park Jane , Hill Corinne , Eng Kenneth , Bareja Rohan , Han Teng , Liu Eric Minwei , Palladino Ann , Di Wei , Gao Dong , Abida Wassim , Beg Shaham , Puca Loredana , Meneses Maximiliano , De Stanchina Elisa , Berger Michael , Gopalan Anuradha , Dow Lukas , Mosquera Juan Miguel , Beltran Himisha , Sternberg Cora , Chi Ping , Scher Howard , Sboner Andrea , Chen Yu , Khurana Ekta 
Published: December 2022

Abstract
In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR) dependence leads to clinically aggressive tumors with few therapeutic options. We used ATAC-seq (assay for transposase-accessible chromatin sequencing), RNA-seq, and DNA sequencing to investigate 22 organoids, six patient-derived xenografts, and 12 cell lines. We identified the well-characterized AR-dependent and neuroendocrine subtypes, as well as two AR-negative/low groups: a Wnt-dependent subtype, and a stem cell–like (SCL) subtype driven by activator protein–1 (AP-1) transcription factors. We used transcriptomic signatures to classify 366 patients, which showed that SCL is the second most common subtype of CRPC after AR-dependent. Our data suggest that AP-1 interacts with the YAP/TAZ and TEAD proteins to maintain subtype-specific chromatin accessibility and transcriptomic landscapes in this group. Together, this molecular classification reveals drug targets and can potentially guide therapeutic decisions.
Citation Format: Fanying Tang, Duo Xu, Shangqian Wang, Chen Khuan Wong, Alexander Martinez-Fundichely, Cindy Lee, Sandra Cohen, Jane Park, Corinne Hill, Kenneth Eng, Rohan Bareja, Teng Han, Eric Minwei Liu, Ann Palladino, Wei Di, Dong Gao, Wassim Abida, Shaham Beg, Loredana Puca, Maximiliano Meneses, Elisa De Stanchina, Michael Berger, Anuradha Gopalan, Lukas Dow, Juan Miguel Mosquera, Himisha Beltran, Cora Sternberg, Ping Chi, Howard Scher, Andrea Sboner, Yu Chen, Ekta Khurana. Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B026.
Abstract B031: PRC2 inhibitor suppresses angiogenesis in Hepatocellular carcinoma (HCC) by up-regulation of anti-angiogenic factors vasohibin1 (VASH1) and tissue inhibitor of metalloproteinases 3 (TIMP-3)
Authors: Zhang Hailong 
Published: December 2022

Abstract
Tumor-associated angiogenesis plays a crucial role in the progression of tumor, especially in highly vascularized cancer, such as Liver hepatocellular carcinoma (LIHC), ovarian cancer, lung cancer, human head and neck cancers. Clinical research has shown that LIHC cells upregulate expression of vascular endothelial growth factor A (VEGFA), and induce proliferation and migration of epithelial cells under hypoxia condition, however, the mechanism of angiogenesis has not been completely elucidated in LIHC, especially in epigenetic regulation level. Polycomb repressive complex 2 (PRC2) is a multi-subunit protein complex that catalyzes the methylation of histone H3 at lysine 27, Enhancer of Zeste homolog 2 (EZH2) is the catalytic subunit, while embryonic ectoderm development (EED) recognizes H3K27me3 and enhance the catalytic activity of EZH2. A recent study suggests PRC2 promote angiogenesis in human ovarian carcinoma, while the detailed mechanism this process has not been illustrated. In this paper, we show BR1763, a potent, selective and orally bioavailable small-molecule inhibitor of EED, inhibits PRC2 activity, promote expression of vasohibin1 (VASH1) and tissue inhibitor of metalloproteinases 3 (TIMP3) in certain Hepatocellular Carcinoma (HCC) cells, and induces tumor growth inhibition by suppression of tumor-associated angiogenesis in vivo.
Citation Format: Hailong Zhang. PRC2 inhibitor suppresses angiogenesis in Hepatocellular carcinoma (HCC) by up-regulation of anti-angiogenic factors vasohibin1 (VASH1) and tissue inhibitor of metalloproteinases 3 (TIMP-3). [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B031.
Abstract IA010: The lncRNA Firre functions as a transcriptional activator from a distance
Authors: Rinn John L. , Much Christian , Lasda Erika , Lewandowski Jordan , Smallegan Michael 
Published: December 2022

Abstract
There are currently over 16,000 long-noncoding RNAs (lncRNAs) annotated in mammalian genomes, a number on par with protein-coding genes. Numerous studies have demonstrated that lncRNAs can influence gene expression programs, but lack the temporal resolution to identify the immediate regulatory events. Thus, even for the most well studied the early and primary targets of lncRNAs remains elusive. Here we describe a multifaceted effort to determine the primary targets of a lncRNA and the underlying temporal dynamics. Our approach combines several genetically defined loss-of and gain-of-function, rescue, and inducible lncRNA models. We further resolved gene regulatory events temporally (30 min to four days). Applying this approach, we find that the lncRNA Firre is an RNA-based transcriptional activator. These transcriptional activation events are not mediated by the epigenetic regulators PRC2, WDR5, or G9A, nor are they due to the proximal binding of the Firre lncRNA. Instead, Firre activates transcription by increasing chromatin accessibility (approximately 30 min after induction) and activating primary target genes (about two hours later). Overall, this study suggests Firre functions as an RNA-based transcriptional activator.
Citation Format: John L. Rinn, Christian Much, Erika Lasda, Jordan Lewandowski, Michael Smallegan. The lncRNA Firre functions as a transcriptional activator from a distance. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA010.