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Jaclyn Andricovich, Stephanie Perkail, Yan Kai, Nicole Casasanta, Weiqun Peng, Alexandros Tzatsos
KDM6A, an X chromosome-encoded histone demethylase and member of the COMPASS-like complex, is frequently mutated in a broad spectrum of malignancies and contributes to oncogenesis with poorly characterized mechanisms. We found that KDM6A loss induced squamous-like, metastatic pancreatic cancer selectively in females through deregulation of the COMPASS-like complex and aberrant activation of super-enhancers regulating ΔNp63, MYC, and RUNX3 oncogenes. This subtype of tumor developed in males had concomitant loss of UTY and KDM6A, suggesting overlapping roles, and points to largely demethylase independent tumor suppressor functions...
March 12, 2018: Cancer Cell
Dong-Li Zhu, Xiao-Feng Chen, Wei-Xin Hu, Shan-Shan Dong, Bing-Jie Lu, Yu Rong, Yi-Xiao Chen, Hao Chen, Hlaing Nwe Thynn, Nai-Ning Wang, Yan Guo, Tie-Lin Yang
RANKL is a key regulator involved in bone metabolism, and a drug target for osteoporosis. The clinical diagnosis and assessment of osteoporosis are mainly based on bone mineral density (BMD). Previous powerful genome-wide association studies (GWASs) have identified multiple intergenic single nucleotide polymorphisms (SNPs) located over 100 kb upstream of RANKL and 65 kb downstream of AKAP11 at 13q14.11 for osteoporosis. Whether these SNPs exert their roles on osteoporosis through RANKL is unknown. In this study, we conducted integrative analyses combining expression quantitative trait locus (eQTL), genomic chromatin interaction (Hi-C), epigenetic annotation and a series of functional assays...
March 12, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Yi Jin, Kenian Chen, Ayla De Paepe, Eva Hellqvist, Aleksandra D Krstic, Lauren Metang, Charlotte Gustafsson, Richard E Davis, Yair M Levy, Rakesh Surapaneni, Ann Wallblom, Hareth Nahi, Robert Mansson, Yin C Lin
Multiple myeloma (MM) is an aggressive cancer that originates from antibody-secreting plasma cells. While genetically and transcriptionally well characterized, the aberrant gene regulatory networks that underpin this disease remain poorly understood. Here, we mapped regulatory elements, open chromatin and transcription factor footprints in primary MM cells. In comparison to normal antibody-secreting cells, MM cells displayed consistent changes in enhancer activity that are connected to super-enhancer (SE)-mediated deregulation of transcription factor (TF) genes...
March 8, 2018: Blood
Clara Lopes Novo, Biola-Maria Javierre, Jonathan Cairns, Anne Segonds-Pichon, Steven W Wingett, Paula Freire-Pritchett, Mayra Furlan-Magaril, Stefan Schoenfelder, Peter Fraser, Peter J Rugg-Gunn
Transcriptional enhancers, including super-enhancers (SEs), form physical interactions with promoters to regulate cell-type-specific gene expression. SEs are characterized by high transcription factor occupancy and large domains of active chromatin, and they are commonly assigned to target promoters using computational predictions. How promoter-SE interactions change upon cell state transitions, and whether transcription factors maintain SE interactions, have not been reported. Here, we used promoter-capture Hi-C to identify promoters that interact with SEs in mouse embryonic stem cells (ESCs)...
March 6, 2018: Cell Reports
Wanju Jiao, Yajun Chen, Huajie Song, Dan Li, Hong Mei, Feng Yang, Erhu Fang, Xiaojing Wang, Kai Huang, Liduan Zheng, Qiangsong Tong
Recent studies reveal the emerging functions of enhancer RNAs (eRNAs) in gene expression. However, the roles of eRNAs in regulating the expression of heparanase (HPSE), an established endo-β-D-glucuronidase essential for cancer invasion and metastasis, still remain elusive. Herein, through comprehensive analysis of publically available FANTOM5 expression atlas and chromatin interaction dataset, we identified a super enhancer and its derived eRNA facilitating the HPSE expression (HPSE eRNA) in cancers. Gain-of-function and loss-of-function experiments indicated that HPSE eRNA facilitated the in vitro and in vivo tumorigenesis and aggressiveness of cancer cells...
March 7, 2018: Oncogene
Jialiang Huang, Kailong Li, Wenqing Cai, Xin Liu, Yuannyu Zhang, Stuart H Orkin, Jian Xu, Guo-Cheng Yuan
Recent studies have highlighted super-enhancers (SEs) as important regulatory elements for gene expression, but their intrinsic properties remain incompletely characterized. Through an integrative analysis of Hi-C and ChIP-seq data, here we find that a significant fraction of SEs are hierarchically organized, containing both hub and non-hub enhancers. Hub enhancers share similar histone marks with non-hub enhancers, but are distinctly associated with cohesin and CTCF binding sites and disease-associated genetic variants...
March 5, 2018: Nature Communications
Emilia Kuuluvainen, Eva Domènech-Moreno, Elina H Niemelä, Tomi P Mäkelä
In cancer, oncogene activation is partly mediated by acquired super-enhancers therefore representing potential targets for inhibition. Super-enhancers are enriched for BRD4 and Mediator and both BRD4 and the Mediator MED12 subunit are disproportionally required for expression of super-enhancer associated genes in stem cells. Here, we find that depletion of Mediator kinase module subunits MED12, and MED13 with MED13L, can be used to reduce expression of cancer acquired super-enhancer genes such as MYC in colon cancer cells with a concomitant decrease in proliferation...
March 5, 2018: Molecular and Cellular Biology
Jia Wang, Xingui Wu, Chao Wei, Xin Huang, Qian Ma, Xiaona Huang, Francesco Faiola, Diana Guallar, Miguel Fidalgo, Tingyuan Huang, Di Peng, Li Chen, Haopeng Yu, Xingyu Li, Junyi Sun, Xinyi Liu, Xiaoxia Cai, Xiao Chen, Ling Wang, Jian Ren, Jianlong Wang, Junjun Ding
Yin Yang 1 (YY1) regulates early embryogenesis and adult tissue formation. However, the role of YY1 in stem cell regulation remains unclear. YY1 has a Polycomb group (PcG) protein-dependent role in mammalian cells. The PcG-independent functions of YY1 are also reported, although their underlying mechanism is still undefined. This paper reports the role of YY1 and BAF complex in the OCT4-mediated pluripotency network in mouse embryonic stem cells (mESCs). The interaction between YY1 and BAF complex promotes mESC proliferation and pluripotency...
February 26, 2018: Stem Cell Reports
Carl Baribault, Kenneth C Ehrlich, V K Chaithanya Ponnaluri, Sriharsa Pradhan, Michelle Lacey, Melanie Ehrlich
DNA methylation can affect tissue-specific gene transcription in ways that are difficult to discern from studies focused on genome-wide analyses of differentially methylated regions (DMRs). To elucidate the variety of associations between differentiation-related DNA hypermethylation and transcription, we used available epigenomic and transcriptomic profiles from 38 human cell/tissue types to focus on such relationships in 94 genes linked to hypermethylated DMRs in myoblasts (Mb). For 19 of the genes, promoter-region hypermethylation in Mb (and often a few heterologous cell types) was associated with gene repression but, importantly, DNA hypermethylation was absent in many other repressed samples...
March 2, 2018: Epigenetics: Official Journal of the DNA Methylation Society
Juexiao Gong, Chuan Qiu, Dan Huang, Yiyan Zhang, Shengyong Yu, Chunping Zeng
Clinical research in coronary artery disease (CAD) primarily focused on genetic variants located in protein-coding regions. Recently, mutations fall within non-coding regions have been suggested to be essential to the pathogenesis of human complex disease. Super enhancer is a densely spaced cluster of transcriptional enhancers located in non-coding regions, which is critical for regulating cell-type specific gene expression. However, the underlying mechanism of the super enhancer single-nucleotide polymorphisms (SNPs) affecting the risk of CAD remains unclear...
February 28, 2018: Journal of Human Genetics
Daniel Gerlach, Ulrike Tontsch-Grunt, Anke Baum, Johannes Popow, Dirk Scharn, Marco H Hofmann, Harald Engelhardt, Onur Kaya, Janina Beck, Norbert Schweifer, Thomas Gerstberger, Johannes Zuber, Fabio Savarese, Norbert Kraut
Bromodomain and extra-terminal (BET) protein inhibitors have been reported as treatment options for acute myeloid leukemia (AML) in preclinical models and are currently being evaluated in clinical trials. This work presents a novel potent and selective BET inhibitor (BI 894999), which has recently entered clinical trials (NCT02516553). In preclinical studies, this compound is highly active in AML cell lines, primary patient samples, and xenografts. HEXIM1 is described as an excellent pharmacodynamic biomarker for target engagement in tumors as well as in blood...
March 1, 2018: Oncogene
Silvia Boffo, Angela Damato, Luigi Alfano, Antonio Giordano
Current treatment for acute myeloid leukemia (AML) is less than optimal, but increased understanding of disease pathobiology and genomics has led to clinical investigation of novel targeted therapies and rational combinations. Targeting the cyclin-dependent kinase 9 (CDK9) pathway, which is dysregulated in AML, is an attractive approach. Inhibition of CDK9 leads to downregulation of cell survival genes regulated by super enhancers such as MCL-1, MYC, and cyclin D1. As CDK9 inhibitors are nonselective, predictive biomarkers that may help identify patients most likely to respond to CDK9 inhibitors are now being utilized, with the goal of improving efficacy and safety...
February 23, 2018: Journal of Experimental & Clinical Cancer Research: CR
Valentina Miano, Giulio Ferrero, Valentina Rosti, Eleonora Manitta, Jamal Elhasnaoui, Giulia Basile, Michele De Bortoli
Estrogen receptor-α (ERα) is a ligand-inducible protein which mediates estrogenic hormones signaling and defines the luminal BC phenotype. Recently, we demonstrated that even in absence of ligands ERα (apoERα) binds chromatin sites where it regulates transcription of several protein-coding and lncRNA genes. Noteworthy, apoERα-regulated lncRNAs marginally overlap estrogen-induced transcripts, thus representing a new signature of luminal BC genes. By the analysis of H3K27ac enrichment in hormone-deprived MCF-7 cells, we defined a set of Super Enhancers (SEs) occupied by apoERα, including one mapped in proximity of the DSCAM-AS1 lncRNA gene...
February 16, 2018: International Journal of Molecular Sciences
Jian-Jun Xie, Yan-Yi Jiang, Yuan Jiang, Chun-Quan Li, Lim-Mei Chee, Omer An, Anand Mayakonda, Ling-Wen Ding, Lin Long, Chun Sun, Le-Hang Lin, Li Chen, Jian-Yi Wu, Zhi-Yong Wu, Qi Cao, Wang-Kai Fang, Wei Yang, Stephen J Meltzer, Henry Yang, Melissa Fullwood, Li-Yan Xu, En-Min Li, De-Chen Lin, H Phillip Koeffler
BACKGROUND & AIMS: Long non-coding RNAs (lncRNAs) are expressed in tissue-specific pattern, but it is not clear how these are regulated. We aimed to identify squamous cell carcinoma (SCC)-specific lncRNAs and investigate mechanisms that control their expression and function. METHODS: We studied expression patterns and functions of 4 SCC-specific lncRNAs. We obtained 113 esophageal SCC (ESCC) and matched non-tumor esophageal tissues from a hospital in Shantou City, China, and performed quantitative reverse transcription PCR assays to measure expression levels of LINC01503...
February 15, 2018: Gastroenterology
Venetia Bigley, Urszula Cytlak, Matthew Collin
The critical functions of dendritic cells (DCs) in immunity and tolerance have been demonstrated in many animal models but their non-redundant roles in humans are more difficult to probe. Human primary immunodeficiency (PID), resulting from single gene mutations, may result in DC deficiency or dysfunction. This relatively recent recognition illuminates the in vivo role of human DCs and the pathophysiology of the associated clinical syndromes. In this review, the development and function of DCs as established in murine models and human in vitro systems, is discussed...
February 13, 2018: Seminars in Cell & Developmental Biology
Jonathan D Brown, Zachary B Feldman, Sean P Doherty, Jaime M Reyes, Peter B Rahl, Charles Y Lin, Quanhu Sheng, Qiong Duan, Alexander J Federation, Andrew L Kung, Saptarsi M Haldar, Richard A Young, Jorge Plutzky, James E Bradner
Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomain-containing protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation...
February 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Michaela C Baldauf, Martin F Orth, Marlene Dallmayer, Aruna Marchetto, Julia S Gerke, Rebeca Alba Rubio, Merve M Kiran, Julian Musa, Maximilian M L Knott, Shunya Ohmura, Jing Li, Nusret Akpolat, Ayse N Akatli, Özlem Özen, Uta Dirksen, Wolfgang Hartmann, Enrique de Alava, Daniel Baumhoer, Giuseppina Sannino, Thomas Kirchner, Thomas G P Grünewald
Ewing sarcoma is an undifferentiated small-round-cell sarcoma. Although molecular detection of pathognomonic EWSR1-ETS fusions such as EWSR1-FLI1 enables definitive diagnosis, substantial confusion can arise if molecular diagnostics are unavailable. Diagnosis based on the conventional immunohistochemical marker CD99 is unreliable due to its abundant expression in morphological mimics. To identify novel diagnostic immunohistochemical markers for Ewing sarcoma, we performed comparative expression analyses in 768 tumors representing 21 entities including Ewing-like sarcomas, which confirmed that CIC-DUX4- , BCOR-CCNB3- , EWSR1-NFATc2- , and EWSR1-ETS -translocated sarcomas are distinct entities, and revealed that ATP1A1 , BCL11B , and GLG1 constitute specific markers for Ewing sarcoma...
January 5, 2018: Oncotarget
Yixiao Gong, Charalampos Lazaris, Theodore Sakellaropoulos, Aurelie Lozano, Prabhanjan Kambadur, Panagiotis Ntziachristos, Iannis Aifantis, Aristotelis Tsirigos
The metazoan genome is compartmentalized in areas of highly interacting chromatin known as topologically associating domains (TADs). TADs are demarcated by boundaries mostly conserved across cell types and even across species. However, a genome-wide characterization of TAD boundary strength in mammals is still lacking. In this study, we first use fused two-dimensional lasso as a machine learning method to improve Hi-C contact matrix reproducibility, and, subsequently, we categorize TAD boundaries based on their insulation score...
February 7, 2018: Nature Communications
Azadeh Hajmirza, Anouk Emadali, Arnaud Gauthier, Olivier Casasnovas, Rémy Gressin, Mary B Callanan
NFκB (Nuclear Factor- κ -light-chain-enhancer of activated B cells) signaling elicits global transcriptional changes by activating cognate promoters and through genome-wide remodeling of cognate regulatory elements called "super enhancers". BET (Bromodomain and Extra-Terminal domain) protein family inhibitor studies have implicated BET protein member BRD4 and possibly other BET proteins in NFκB-dependent promoter and super-enhancer modulation. Members of the BET protein family are known to bind acetylated chromatin to facilitate access by transcriptional regulators to chromatin, as well as to assist the activity of transcription elongation complexes via CDK9/pTEFb...
February 6, 2018: Biomedicines
Philip Eliades, Brian J Abraham, Zhenyu Ji, David M Miller, Camilla L Christensen, Nicholas Kwiatkowski, Raj Kumar, Ching Ni Njauw, Michael Taylor, Benchun Miao, Tinghu Zhang, Kwok-Kin Wong, Nathanael S Gray, Richard A Young, Hensin Tsao
Cutaneous melanoma is an aggressive tumor which accounts for most of the skin cancer deaths. Among the physiological barriers against therapeutic success is a strong survival program driven by genes that specify melanocyte identity such as MITF - a phenomenon known in melanoma biology as "lineage dependency." MITF overexpression is occasionally explained by gene amplification, but here we demonstrate that "super-enhancers" are also important determinants of MITF overexpression in some melanoma cell lines and tumors...
February 2, 2018: Journal of Investigative Dermatology
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