tbuckley/cabot-search huggingface dataset:
Epigenetic Regulation by <i>Suv4-20h1</i> in Cardiopulmonary Progenitor Cells Is Required to Prevent Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease
Authors: Hui Qi, Hang Liu, Soni Savai Pullamsetti, Stefan Günther, Carsten Kuenne, Ann Atzberger, Natascha Sommer, Stefan Hadzic, Andreas Günther, Norbert Weissmann, Yonggang Zhou, Xuejun Yuan, Thomas Braun
Journal: Circulation (2021)

The pathogenesis of life-threatening cardiopulmonary diseases such as pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) originates from a complex interplay of environmental factors and genetic predispositions that is not fully understood. Likewise, little is known about developmental abnormalities or epigenetic dysregulations that might predispose for PH or COPD in adult individuals.To identify pathology-associated epigenetic alteration in diseased lung tissues, we screened a cohort of human patients with PH and COPD for changes of histone modifications by immunofluorescence staining. To analyze the function of H4K20me2/3 in lung pathogenesis, we developed a series of Suv4-20h1 knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types, followed by hemodynamic studies and morphometric assessment of tissue samples. Molecular, cellular, and biochemical techniques were applied to analyze the function of Suv4-20h1-dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives.We discovered a strong reduction of the histone modifications of H4K20me2/3 in human patients with COPD but not patients with PH that depend on the activity of the H4K20 di-methyltransferase SUV4-20H1. Loss of Suv4-20h1 in cardiopulmonary progenitor cells caused a COPD-like/PH phenotype in mice including the formation of perivascular tertiary lymphoid tissue and goblet cell hyperplasia, hyperproliferation of smooth muscle cells/myofibroblasts, impaired alveolarization and maturation defects of the microvasculature leading to massive right ventricular dilatation and premature death. Mechanistically, SUV4-20H1 binds directly to the 5'-upstream regulatory element of the superoxide dismutase 3 (Sod3) gene to repress its expression. Increased levels of the extracellular SOD3 enzyme in Suv4-20h1 mutants increases hydrogen peroxide concentrations, causing vascular defects and impairing alveolarization.Our findings reveal a pivotal role of the histone modifier SUV4-20H1 in cardiopulmonary codevelopment and uncover the developmental origins of cardiopulmonary diseases. We assume that the study will facilitate the understanding of pathogenic events causing PH and COPD and aid the development of epigenetic drugs for the treatment of cardiopulmonary diseases.
Adaptive Prediction for Social Contexts: The Cerebellar Contribution to Typical and Atypical Social Behaviors
Authors: Catherine J. Stoodley, Peter T. Tsai
Journal: Annual Review of Neuroscience (2021)

Social interactions involve processes ranging from face recognition to understanding others’ intentions. To guide appropriate behavior in a given context, social interactions rely on accurately predicting the outcomes of one's actions and the thoughts of others. Because social interactions are inherently dynamic, these predictions must be continuously adapted. The neural correlates of social processing have largely focused on emotion, mentalizing, and reward networks, without integration of systems involved in prediction. The cerebellum forms predictive models to calibrate movements and adapt them to changing situations, and cerebellar predictive modeling is thought to extend to nonmotor behaviors. Primary cerebellar dysfunction can produce social deficits, and atypical cerebellar structure and function are reported in autism, which is characterized by social communication challenges and atypical predictive processing. We examine the evidence that cerebellar-mediated predictions and adaptation play important roles in social processes and argue that disruptions in these processes contribute to autism.
Proton pump inhibitors and gastric cancer: a population-based cohort study
Authors: Jigar Patel, Ivan Berezowski, Rajesh Naidu Janapala, Ali Pourmand
Journal: Gut (2021)

We read with great interest the recent article by Seo et al regarding the association of proton pump inhibitors (PPI) and gastric cancer.1 We want to congratulate the authors for their exemplary work as the prevalence of PPI in current clinical practice cannot be overstated. After reviewing the article, we have some comments to share with you.

As mentioned in the Methods section and also in figure 1, the target cohort was defined as ‘new PPI users’ who were prescribed PPI for more than 30 consecutive days. Although we understood that the subjects underwent 365 days of continuous observation to be classified as new PPI users, we are curious to know if the remote history of PPI use (>365 days ago) was taken into consideration before enrolment into the target cohort. The authors have defined index date as the first day of a new …
Abstract 238: Exhaustive tumor specific antigen detection with RNAseq
Authors: Michael Sharpnack, Travis Johnson, Robert Chalkley, Zhi Han, David Carbone, Kun Huang, Kai He
Journal: Cancer Research (2021)

Abstract Background: Tumor specific antigen (TSA) identification in human cancer predicts response to immunotherapy and provides vaccine targets for precision medicine. In addition to neoantigens from somatic coding mutations, numerous non-mutated TSAs can elicit T-cell responses but are often overlooked by current methods. We present a method that accurately and comprehensively predict TSAs from RNAseq data regardless of mutation status. Methods: HLA-I genotypes were predicted with seq2HLA. RNAseq fastq files were translated into all possible peptides of length 8-11, and peptides with high expression in the tumor and comparatively low expression in normal were tested for their MHC-I binding potential with netMHCpan-4.0. We defined our predicted TSA by i) high expression in tumor samples, ii) low expression in normal samples, and iii) high predicted patient-specific MHC-I binding affinity. Results: We developed a novel pipeline for TSA prediction from RNAseq that is not limited to mutation-derived TSAs. This pipeline was used to predict all possible unique peptides size 8-11 on previously published murine and human lung and lymphoma tumors then validated on matched tumor and control lung adenocarcinoma (LUAD) samples. This pipeline is able to predict TSAs in MHC-I ligand-purified proteomics data with favorable performance to existing methods. Furthermore, neoantigens predicted by exomeSeq are typically poorly expressed at the RNA level, (28% of predicted neoantigens with &amp;gt;0 expression, mean of 15.6 reads/sample) and a fraction of them (47/6,928, 0.68%) are expressed in matched normal samples. Finally, a set of 6 TSAs are expressed in 22/39 (56%) of LUAD tumors and represent attractive vaccine targets. Conclusion: Direct quantification of RNAseq evidence of the potential peptidome in matched tumor and control RNAseq samples, via our novel pipeline, allows for exhaustive detection of TSAs. Citation Format: Michael Sharpnack, Travis Johnson, Robert Chalkley, Zhi Han, David Carbone, Kun Huang, Kai He. Exhaustive tumor specific antigen detection with RNAseq [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 238.
Elevated retrotransposon activity and genomic instability in primed pluripotent stem cells
Authors: Haifeng Fu, Weiyu Zhang, Niannian Li, Jiao Yang, Xiaoying Ye, Chenglei Tian, Xinyi Lu, Lin Liu
Journal: Genome biology (2021)

Abstract Background Naïve and primed pluripotent stem cells (PSCs) represent two different pluripotent states. Primed PSCs following in vitro culture exhibit lower developmental potency as evidenced by failure in germline chimera assays, unlike mouse naïve PSCs. However, the molecular mechanisms underlying the lower developmental competency of primed PSCs remain elusive. Results We examine the regulation of telomere maintenance, retrotransposon activity, and genomic stability of primed PSCs and compare them with naïve PSCs. Surprisingly, primed PSCs only minimally maintain telomeres and show fragile telomeres, associated with declined DNA recombination and repair activity, in contrast to naïve PSCs that robustly elongate telomeres. Also, we identify LINE1 family integrant L1Md_T as naïve-specific retrotransposon and ERVK family integrant IAPEz to define primed PSCs, and their transcription is differentially regulated by heterochromatic histones and Dnmt3b. Notably, genomic instability of primed PSCs is increased, in association with aberrant retrotransposon activity. Conclusions Our data suggest that fragile telomere, retrotransposon-associated genomic instability, and declined DNA recombination repair, together with reduced function of cell cycle and mitochondria, increased apoptosis, and differentiation properties may link to compromised developmental potency of primed PSCs, noticeably distinguishable from naïve PSCs.
Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia–Reperfusion Injury
Authors: Meredith A. Redd, Sarah E. Scheuer, Natalie J. Saez, Yusuke Yoshikawa, Han Sheng Chiu, Ling Gao, Mark Hicks, Jeanette E. Villanueva, Yashutosh Joshi, Chun Yuen Chow, Gabriel Cuellar-Partida, Jason N. Peart, Louise E. See Hoe, Xiaoli Chen, Yuliangzi Sun, Jacky Y. Suen, Robert J. Hatch, Ben Rollo, Di Xia, Mubarak A.H. Alzubaidi, Snezana Maljevic, Gregory A. Quaife-Ryan, James E. Hudson, Enzo R. Porrello, Melanie Y. White, Stuart J. Cordwell, John F. Fraser, Steven Petrou, Melissa E. Reichelt, Walter G. Thomas, Glenn F. King, Peter S. Macdonald, Nathan J. Palpant
Journal: Circulation (2021)

Background: Ischemia–reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH, which can reach as low as 6.0 to 6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly affects cardiac function. Methods: We used genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole-organ level. Human induced pluripotent stem cell–derived cardiomyocytes as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and postconditioning therapeutic agents. Results: Analysis of human complex trait genetics indicates that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using human induced pluripotent stem cell–derived cardiomyocytes in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacologic inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and 2 models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as preconditioning or postconditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no effect on cardiac ion channels regulating baseline electromechanical coupling and physiologic performance. Conclusions: Our data provide compelling evidence for a novel pharmacologic strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.
Abstract 2427: Identification of transcription factors activated in glioblastoma multiforme
Authors: Zexun Wu, Shannon Schreiner, Peggy J. Farnham, Suhn K. Rhie
Journal: Cancer Research (2021)

Abstract Introduction Glioblastoma multiforme (GBM) is the most common intrinsic brain tumor in adults and is universally fatal. Our strategy to study the molecular mechanisms leading to GBM is to investigate the role of transcription factors (TFs) that are differentially expressed between normal and GBM. Previous studies have shown that ZFX is a key TF that shows increased expression in GBM. However, the role of ZFX, and the identity of TFs that may work with ZFX, in driving GBM carcinogenesis is not yet understood. Materials and methods: ChIP-seq was performed to determine ZFX binding sites in the U87 GBM cancer cell line. RNA-seq datasets generated from GBM tissues by The Cancer Genome Atlas (TCGA) were analyzed to identify TFs showing increased expression in GBM. Publicly available H3K27ac chromatin immunoprecipitation (ChIP-seq) and Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) datasets generated from GBM tissues were analyzed to identify active enhancers and TFs that bind to GBM enhancers. Results: We found that a majority of ZFX binding sites in GBM are located at promoters, with ~1000 binding sites being at non-promoter regions. An overlap analysis of ZFX binding sites in multiple cancer cell types showed that a high percentage of ZFX-binding sites at promoter regions are shared across cell types whereas hundreds of GBM-specific binding sites are located at non-promoter regions. Using TCGA GBM RNA-seq datasets, we next identified differentially expressed TFs. For example, we found that MTY1L and NEUROD2, which have been reported to be tumor suppressors, are downregulated while HOX family TFs are upregulated in GBM tissues, as compared to normal tissues. We also identified thousands of enhancers specifically active in GBM, as compared to normal cells, using H3K27ac ChIP-seq and ATAC-seq datasets. TF motif analysis of the identified enhancers revealed that motifs of Basic Leucine Zipper Domain (bZIP), CAAT box-binding transcription factor (CTF), homeobox (HOX), signal transducer and activator of transcription (STAT), and helix-turn-helix (HTH) family were enriched. Conclusion: By integrating transcriptomic and epigenomic datasets, we identified and characterized TFs activated in GBM. We are currently investigating how ZFX cooperates with the TFs we identified as bound to the GBM-specific enhancers. These studies will provide insight into the molecular mechanisms underlying GBM. Citation Format: Zexun Wu, Shannon Schreiner, Peggy J. Farnham, Suhn K. Rhie. Identification of transcription factors activated in glioblastoma multiforme [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 2427.
“Driver-passenger” bacteria and their metabolites in the pathogenesis of colorectal cancer
Authors: Marion Avril, R. William DePaolo
Journal: Gut Microbes (2021)

Colorectal cancer (CRC) is a significant public health problem accounting for about 10% of all new cancer cases globally. Though genetic and epigenetic factors influence CRC, the gut microbiota acts as a significant component of the disease's etiology. Further research is still needed to clarify the specific roles and identify more bacteria related to CRC development. This review aims to provide an overview of the "driver-passenger" model of CRC. The colonization and active invasion of the "driver(s)" bacteria cause damages allowing other commensals, known as "passengers," or their by-products, i.e., metabolites, to pass through the epithelium . This review will not only focus on the species of bacteria implicated in this model but also on their biological functions implicated in the occurrence of CRC, such as forming biofilms, mucus, penetration and production of enterotoxins and genotoxins.
Abstract 535: Molecular profiling of brainstem gliomas by liquid biopsy
Authors: Changcun Pan, Tian Li, Liping Jiang, Hai Yan, Liwei Zhang
Journal: Cancer Research (2021)

Abstract Background: Brainstem gliomas are heterogeneous diseases, many of which are difficult to safely resect and have limited treatment options due to their location. These constraints pose challenges to biopsy, which limits the use of routine molecular profiling and identification of personalized therapies. Here, we explored the potential of sequencing of circulating tumor DNA (ctDNA) isolated from the cerebrospinal fluid (CSF) of brainstem glioma patients as a less invasive approach for tumor molecular profiling. Cohorts and Methods:A retrospective analysis of brainstem glioma patients with CSF and tumor tissue available was completed. CSF was obtained from patients either intraoperatively (91.2%, 52/57), from ventricular-peritoneal shunt (3.5%, 2/57), or by lumbar puncture (5.3%, 3/57), all prior to surgical manipulation of the tumor. Deep panel sequencing of glioma-associated genes was performed on CSF-derived ctDNA and, where available, matched blood and tumor DNA from 57 patients, including nine medullary and 23 diffuse intrinsic pontine gliomas (DIPG). In addition, we have now completed a prospective study, in which 12 preoperative CSF samples were obtained from lumbar puncture and used to isolate and characterize ctDNA. Results: In the retrospective analysis, at least one tumor-specific mutation was detected in over 82.5% of CSF ctDNA samples (47/57). In cases with primary tumors harboring at least one mutation, alterations were identified in the CSF ctDNA of 97.3% of cases (36/37). In over 83% (31/37) of cases, all primary tumor alterations were detected in the CSF, and in 91.9% (34/37) of cases, at least half of the alterations were identified. Among ten patients found to have primary tumors negative for mutations, 30% (3/10) had detectable somatic alterations in the CSF. Finally, mutation detection using plasma ctDNA was less sensitive than sequencing the CSF ctDNA (38% vs. 100%, respectively). In the prospective study, at least one tumor-specific mutation was detected in over 83.3% of CSF ctDNA samples (10/12), which is consistent with the data from the retrospective cohort. Conclusion: Our study indicates that deep sequencing of CSF ctDNA is a reliable technique for detecting tumor-specific alterations in brainstem tumors. This approach may offer an alternative approach to stereotactic biopsy for molecular profiling of brainstem tumors. Citation Format: Changcun Pan, Tian Li, Liping Jiang, Hai Yan, Liwei Zhang. Molecular profiling of brainstem gliomas by liquid biopsy [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 535.
YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m6A modification to activate NF-κB and promote the malignant progression of glioma
Authors: Rui-Chao Chai, Yu-Zhou Chang, Xin Chang, Bo Pang, Song Yuan An, Ke-Nan Zhang, Yuan-Hao Chang, Tao Jiang, Yong-Zhi Wang
Journal: Journal of Hematology & Oncology (2021)

Abstract Background The prognosis for diffuse gliomas is very poor and the mechanism underlying their malignant progression remains unclear. Here, we aimed to elucidate the role and mechanism of the RNA N 6,2′- O -dimethyladenosine (m 6 A) reader, YTH N 6-methyladenosine RNA binding protein 2 (YTHDF2), in regulating the malignant progression of gliomas. Methods YTHDF2 mRNA levels and functions were assessed using several independent datasets. Western blotting, quantitative polymerase chain reaction, and immunohistochemistry were used to evaluate the expression levels of YTHDF2 and other molecules in human and mouse tumor tissues and cells. Knockdown and overexpression were used to evaluate the effects of YTHDF2, methyltransferase-like 3 (METTL3), and UBX domain protein 1 (UBXN1) on glioma malignancy in cell and orthotopic xenograft models. RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were performed to study the mechanisms underlying the oncogenic role of YTHDF2. Results YTHDF2 expression was positively associated with a higher malignant grade and molecular subtype of glioma and poorer prognosis. YTHDF2 promoted the malignant progression of gliomas in both in vitro and in vivo models. Mechanistically, YTHDF2 accelerated UBXN1 mRNA degradation via METTL3-mediated m 6 A, which, in turn, promoted NF-κB activation. We further revealed that UBXN1 overexpression attenuated the oncogenic effect of YTHDF2 overexpression and was associated with better survival in patients with elevated YTHDF2 expression. Conclusions Our findings confirmed that YTHDF2 promotes the malignant progression of gliomas and revealed important insight into the upstream regulatory mechanism of NF-κB activation via UBXN1 with a primary focus on m 6 A modification.
Abstract 1163: Histone deacetylase inhibitors as potential differentiation therapy in lung adenocarcinoma
Authors: Wai Chin Chong, Vijesh Vaghjiani, Jason Edward Cain
Journal: Cancer Research (2021)

Abstract Impaired differentiation is a common feature of cancer. In contrast to chemotherapy, the goal of differentiation therapy is to exhaust the malignant potential of tumour cells through the reactivation of developmental programs rather than cell death. The Switch/Sucrose Non-Fermentable (SWI/SNF) DNA remodelling complexes play a vital role in regulating cellular differentiation and have been strongly implicated in cancer. SWI/SNF complexes bind to the DNA-histone scaffold and initiate transcription via the recruitment of vital cellular transcriptional machinery including histone acetyltransferases. Next-generation sequencing has identified mutations in at least 10 genes encoding subunits of the SWI/SNF complexes that are recurrently mutated in cancers originating in nearly every body tissue, collectively occurring in &amp;gt;25% of all human malignancies. Lung adenocarcinoma (LAC) accounts for &amp;gt;40% of all lung cancers and has an 18% of overall 5-year survival. Mutations in SMARCA4 are believed to occur in &amp;gt;12% of LAC. Using a panel of characterized human LAC cell lines we show a marked sensitivity of the HDACi, HDACi, exclusively to SMARCA4-null LAC only. This is preceded by increased H3K27ac, decreased H3K27me3 and decreased EZH2 expression. Sustained low-dose panobinostat treatment of SMARCA4-mutant LAC cell lines, results in unique gene expression changes consistent with differentiation, not observed in SMARCA4 wildtype lines. To further demonstrate the specific dependence of loss of SMARCA4 on response to HDACi, we generated three isogenic cell lines using CRISPR KO. H358, H441 and H2009 SMARCA4 KO LAC cell lines were markedly more sensitive to panobinostat than their wildtype parental lines. Lastly, panobinostat treatment results in tumour growth arrest and increased survival in SMARCA4-deficient LAC cell line xenografts and PDX models in vivo but not in SMARCA4-intact LAC models. Together, these data suggest that SMARCA4-deficient LAC are dependent on HDAC activity to maintain an undifferentiated state and are therefore highly susceptible to epigenetic differentiation therapy. Citation Format: Wai Chin Chong, Vijesh Vaghjiani, Jason Edward Cain. Histone deacetylase inhibitors as potential differentiation therapy in lung adenocarcinoma [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 1163.