Integrative Framework for Identification of Key Cell Identity Genes Uncovers
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Variants of the Elongator Protein 3 (ELP3) Gene Are Associated with Motor Neuron Degeneration
Human Molecular Genetics, 2009, Vol. 18, No. 3 472–481 doi:10.1093/hmg/ddn375 Advance Access published on November 7, 2008 Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration Claire L. Simpson1,{, Robin Lemmens4,{, Katarzyna Miskiewicz6,7, Wendy J. Broom8, Valerie K. Hansen1, Paul W.J. van Vught9, John E. Landers8, Peter Sapp8,11, Ludo Van Den Bosch4,5, Joanne Knight3, Benjamin M. Neale3, Martin R. Turner1, Jan H. Veldink9, Roel A. Ophoff10,12, Vineeta B. Tripathi1, Ana Beleza1, Meera N. Shah1, Petroula Proitsi2, Annelies Van Hoecke4,5, Peter Carmeliet5, H. Robert Horvitz11, P. Nigel Leigh1, Christopher E. Shaw1, Leonard H. van den Berg9, Pak C. Sham13, John F. Powell2, Patrik Verstreken6,7, Robert H. Brown Jr8, Wim Robberecht4,5 and Ammar Al-Chalabi1,Ã 1Department of Neurology, 2Department of Neuroscience, MRC Centre for Neurodegeneration Research and 3MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London SE5 8AF, UK, 4Service of Neurology (University Hospital Leuven) and Laboratory for Neurobiology, Section of Experimental Neurology, University of Leuven, Leuven B-3000, Belgium, 5Vesalius Research Center, Flanders Institute for Biotechnology (VIB) and 6Center for Human Genetics, Laboratory of Neuronal Communication, KU Leuven, Leuven B-3000, Belgium, 7Department of Molecular and Developmental Genetics, VIB, Leuven B-3000, Belgium, 8Cecil B Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, -
Genome-Wide Analysis of Differentially Expressed Lncrna in Sporadic Parathyroid Tumors
Osteoporosis International (2019) 30:1511–1519 https://doi.org/10.1007/s00198-019-04959-y ORIGINAL ARTICLE Genome-wide analysis of differentially expressed lncRNA in sporadic parathyroid tumors T. Jiang1 & B. J. Wei2,3 & D. X. Zhang1 & L. Li4 & G. L. Qiao5 & X. A. Yao1 & Z. W. Chen6 & X. Liu6 & X. Y. Du6 Received: 4 December 2018 /Accepted: 25 March 2019 /Published online: 10 April 2019 # International Osteoporosis Foundation and National Osteoporosis Foundation 2019 Abstract Summary Diagnosis of parathyroid carcinoma on histological examination is challenging. Thousands of differentially expressed lncRNAs were identified on the microarray data between parathyroid cancer and adenoma samples. Four lncRNAs were signif- icantly dysregulated in further validation. The BlncRNA score^ calculated from these lncRNAs differentiated parathyroid carcino- mas from adenomas. LncRNAs serve as biomarkers for parathyroid cancer diagnosis. Introduction Diagnosis of parathyroid carcinoma (PC) on histological examination is challenging. LncRNA profile study was conducted to find diagnostic biomarkers for PC. Methods LncRNA arrays containing 91,007 lncRNAs as well as 29,857 mRNAs were used to assess parathyroid specimen (5 carcinomas and 6 adenomas). Bioinformatics analyses were also conducted to compare the microarray results between parathyroid carcinomas and adenomas (PAs). Differentially expressed lncRNAs of 11 PCs and 31 PAs were validated by real-time quantitative PCR. Results On the microarray data between PC and PA samples (fold change ≥ 2, P < 0.05), 1809 differentially expressed lncRNAs and 1349 mRNAs also were identified. All carcinomas were clustered in the same group by clustering analysis using dysregulated lncRNAs or mRNAs. Four lncRNAs (LINC00959, lnc-FLT3-2:2, lnc-FEZF2-9:2, and lnc-RP11-1035H13.3.1-2:1) identified were significantly dysregulated in further RT-PCR validation. -
ACTL6A Promotes the Proliferation of Esophageal Squamous Cell Carcinoma Cells and Correlates with Poor Clinical Outcomes
OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH ACTL6A Promotes the Proliferation of Esophageal Squamous Cell Carcinoma Cells and Correlates with Poor Clinical Outcomes This article was published in the following Dove Press journal: OncoTargets and Therapy Rui-zhe Li1 Background: ACTL6A, a regulatory subunit of ATP-dependent chromatin-remodeling Yun-yun Li1,2 complexes SWI/SNF, has been identified as a central oncogenic driver in many tumor types. Hui Qin1 Materials and Methods: We used immunohistochemistry (IHC) to detect ACTL6A Shan-shan Li1 expression in esophageal squamous cell carcinoma (ESCC) tissues. Then, the effect of ACTL6A on proliferation and DNA synthesis was explored by using cell counting kit 8 1 Department of Pathology, School of (CCK8) and EdU retention assays. The potential oncogenic mechanism of ACTL6A in Basic Medical Sciences, Zhengzhou University and First Affiliated Hospital of ESCC cells was also analyzed by flow cytometry and Western blotting. We further estab Zhengzhou University, Zhengzhou, lished an ESCC xenograft mouse model to validate the in vitro results. Henan 450000, People’s Republic of China; 2Department of Stomatology, First Results: ACTL6A expression, localized in cancer cell nuclei, was markedly higher in ESCC Affiliated Hospital of Zhengzhou tissues than in the corresponding noncancerous tissues (P<0.001) and was positively asso University, Zhengzhou, Henan 450000, ciated with tumor size, histological differentiation, T stage and tumor-node-metastasis People’s Republic of China (TNM) stage. Kaplan–Meier analysis revealed that high ACTL6A expression was signifi cantly associated with poor overall survival (OS) (P = 0.008, HR= 2.562, 95% CI: 1.241– 5.289), and decision curve analysis (DCA) demonstrated that ACTL6A could increase the clinical prognostic efficiency of the original clinical prediction model. -
Analysis of Gene Expression Data for Gene Ontology
ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION A Thesis Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Master of Science Robert Daniel Macholan May 2011 ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION Robert Daniel Macholan Thesis Approved: Accepted: _______________________________ _______________________________ Advisor Department Chair Dr. Zhong-Hui Duan Dr. Chien-Chung Chan _______________________________ _______________________________ Committee Member Dean of the College Dr. Chien-Chung Chan Dr. Chand K. Midha _______________________________ _______________________________ Committee Member Dean of the Graduate School Dr. Yingcai Xiao Dr. George R. Newkome _______________________________ Date ii ABSTRACT A tremendous increase in genomic data has encouraged biologists to turn to bioinformatics in order to assist in its interpretation and processing. One of the present challenges that need to be overcome in order to understand this data more completely is the development of a reliable method to accurately predict the function of a protein from its genomic information. This study focuses on developing an effective algorithm for protein function prediction. The algorithm is based on proteins that have similar expression patterns. The similarity of the expression data is determined using a novel measure, the slope matrix. The slope matrix introduces a normalized method for the comparison of expression levels throughout a proteome. The algorithm is tested using real microarray gene expression data. Their functions are characterized using gene ontology annotations. The results of the case study indicate the protein function prediction algorithm developed is comparable to the prediction algorithms that are based on the annotations of homologous proteins. -
The Structural Basis for Selective Binding of Non-Methylated Cpg Islands by the CFP1 CXXC Domain
ARTICLE Received 13 Dec 2010 | Accepted 9 Feb 2011 | Published 8 Mar 2011 DOI: 10.1038/ncomms1237 The structural basis for selective binding of non-methylated CpG islands by the CFP1 CXXC domain Chao Xu1,*, Chuanbing Bian1,*, Robert Lam1, Aiping Dong1 & Jinrong Min1,2 CFP1 is a CXXC domain-containing protein and an essential component of the SETD1 histone H3K4 methyltransferase complex. CXXC domain proteins direct different chromatin-modifying activities to various chromatin regions. Here, we report crystal structures of the CFP1 CXXC domain in complex with six different CpG DNA sequences. The crescent-shaped CFP1 CXXC domain is wedged into the major groove of the CpG DNA, distorting the B-form DNA, and interacts extensively with the major groove of the DNA. The structures elucidate the molecular mechanism of the non-methylated CpG-binding specificity of the CFP1 CXXC domain. The CpG motif is confined by a tripeptide located in a rigid loop, which only allows the accommodation of the non-methylated CpG dinucleotide. Furthermore, we demonstrate that CFP1 has a preference for a guanosine nucleotide following the CpG motif. 1 Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada. 2 Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. *These authors contributed equally to this work. Correspondence and requests for materials should be addressed to J.M. (email: [email protected]). NATURE COMMUNICATIONS | 2:227 | DOI: 10.1038/ncomms1237 | www.nature.com/naturecommunications © 2011 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms1237 pG islands contain a high density of CpG content and embrace the promoters of most genes in vertebrate genomes1. -
New Approaches to Functional Process Discovery in HPV 16-Associated Cervical Cancer Cells by Gene Ontology
Cancer Research and Treatment 2003;35(4):304-313 New Approaches to Functional Process Discovery in HPV 16-Associated Cervical Cancer Cells by Gene Ontology Yong-Wan Kim, Ph.D.1, Min-Je Suh, M.S.1, Jin-Sik Bae, M.S.1, Su Mi Bae, M.S.1, Joo Hee Yoon, M.D.2, Soo Young Hur, M.D.2, Jae Hoon Kim, M.D.2, Duck Young Ro, M.D.2, Joon Mo Lee, M.D.2, Sung Eun Namkoong, M.D.2, Chong Kook Kim, Ph.D.3 and Woong Shick Ahn, M.D.2 1Catholic Research Institutes of Medical Science, 2Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul; 3College of Pharmacy, Seoul National University, Seoul, Korea Purpose: This study utilized both mRNA differential significant genes of unknown function affected by the display and the Gene Ontology (GO) analysis to char- HPV-16-derived pathway. The GO analysis suggested that acterize the multiple interactions of a number of genes the cervical cancer cells underwent repression of the with gene expression profiles involved in the HPV-16- cancer-specific cell adhesive properties. Also, genes induced cervical carcinogenesis. belonging to DNA metabolism, such as DNA repair and Materials and Methods: mRNA differential displays, replication, were strongly down-regulated, whereas sig- with HPV-16 positive cervical cancer cell line (SiHa), and nificant increases were shown in the protein degradation normal human keratinocyte cell line (HaCaT) as a con- and synthesis. trol, were used. Each human gene has several biological Conclusion: The GO analysis can overcome the com- functions in the Gene Ontology; therefore, several func- plexity of the gene expression profile of the HPV-16- tions of each gene were chosen to establish a powerful associated pathway, identify several cancer-specific cel- cervical carcinogenesis pathway. -
Molecular Basis for the Distinct Cellular Functions of the Lsm1-7 and Lsm2-8 Complexes
bioRxiv preprint doi: https://doi.org/10.1101/2020.04.22.055376; this version posted April 23, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Molecular basis for the distinct cellular functions of the Lsm1-7 and Lsm2-8 complexes Eric J. Montemayor1,2, Johanna M. Virta1, Samuel M. Hayes1, Yuichiro Nomura1, David A. Brow2, Samuel E. Butcher1 1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA. 2Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Correspondence should be addressed to E.J.M. ([email protected]) and S.E.B. ([email protected]). Abstract Eukaryotes possess eight highly conserved Lsm (like Sm) proteins that assemble into circular, heteroheptameric complexes, bind RNA, and direct a diverse range of biological processes. Among the many essential functions of Lsm proteins, the cytoplasmic Lsm1-7 complex initiates mRNA decay, while the nuclear Lsm2-8 complex acts as a chaperone for U6 spliceosomal RNA. It has been unclear how these complexes perform their distinct functions while differing by only one out of seven subunits. Here, we elucidate the molecular basis for Lsm-RNA recognition and present four high-resolution structures of Lsm complexes bound to RNAs. The structures of Lsm2-8 bound to RNA identify the unique 2′,3′ cyclic phosphate end of U6 as a prime determinant of specificity. In contrast, the Lsm1-7 complex strongly discriminates against cyclic phosphates and tightly binds to oligouridylate tracts with terminal purines. -
Bppart and Bpmax: RNA-RNA Interaction Partition Function and Structure Prediction for the Base Pair Counting Model
BPPart and BPMax: RNA-RNA Interaction Partition Function and Structure Prediction for the Base Pair Counting Model Ali Ebrahimpour-Boroojeny, Sanjay Rajopadhye, and Hamidreza Chitsaz ∗ Department of Computer Science, Colorado State University Abstract A few elite classes of RNA-RNA interaction (RRI), with complex roles in cellular functions such as miRNA-target and lncRNAs in human health, have already been studied. Accordingly, RRI bioinfor- matics tools tailored for those elite classes have been proposed in the last decade. Interestingly, there are somewhat unnoticed mRNA-mRNA interactions in the literature with potentially drastic biological roles. Hence, there is a need for high-throughput generic RRI bioinformatics tools. We revisit our RRI partition function algorithm, piRNA, which happens to be the most comprehensive and computationally-intensive thermodynamic model for RRI. We propose simpler models that are shown to retain the vast majority of the thermodynamic information that piRNA captures. We simplify the energy model and instead consider only weighted base pair counting to obtain BPPart for Base-pair Partition function and BPMax for Base-pair Maximization which are 225 and 1350 faster ◦ × × than piRNA, with a correlation of 0.855 and 0.836 with piRNA at 37 C on 50,500 experimentally charac- terized RRIs. This correlation increases to 0.920 and 0.904, respectively, at 180◦C. − Finally, we apply our algorithm BPPart to discover two disease-related RNAs, SNORD3D and TRAF3, and hypothesize their potential roles in Parkinson's disease and Cerebral Autosomal Dominant Arteri- opathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). 1 Introduction Since mid 1990s with the advent of RNA interference discovery, RNA-RNA interaction (RRI) has moved to the spotlight in modern, post-genome biology. -
Increased ACTL6A Occupancy Within Mswi/SNF Chromatin Remodelers
bioRxiv preprint doi: https://doi.org/10.1101/2021.03.22.435873; this version posted March 22, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma Chiung-Ying Chang1,2,7, Zohar Shipony3,7, Ann Kuo1,2, Kyle M. Loh4,5, William J. Greenleaf3,6, Gerald R. Crabtree1,2,5* 1Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA. 2Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA. 3Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. 4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. 5Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA. 6Department of Applied Physics, Stanford University, Stanford, California 94305, USA. 7These authors contributed equally. *Corresponding author: Gerald R. Crabtree, [email protected] Summary Mammalian SWI/SNF (BAF) chromatin remodelers play dosage-sensitive roles in many human malignancies and neurologic disorders. The gene encoding the BAF subunit, ACTL6A, is amplified at an early stage in the development of squamous cell carcinomas (SCCs), but its oncogenic role remains unclear. Here we demonstrate that ACTL6A overexpression leads to its stoichiometric assembly into BAF complexes and drives its interaction and engagement with specific regulatory regions in the genome. In normal epithelial cells, ACTL6A was sub-stoichiometric to other BAF subunits. However, increased ACTL6A levels by ectopic expression or in SCC cells led to near-saturation of ACTL6A within BAF complexes. -
Loss of Fam60a, a Sin3a Subunit, Results in Embryonic Lethality and Is Associated with Aberrant Methylation at a Subset of Gene
RESEARCH ARTICLE Loss of Fam60a, a Sin3a subunit, results in embryonic lethality and is associated with aberrant methylation at a subset of gene promoters Ryo Nabeshima1,2, Osamu Nishimura3,4, Takako Maeda1, Natsumi Shimizu2, Takahiro Ide2, Kenta Yashiro1†, Yasuo Sakai1, Chikara Meno1, Mitsutaka Kadota3,4, Hidetaka Shiratori1†, Shigehiro Kuraku3,4*, Hiroshi Hamada1,2* 1Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan; 2Laboratory for Organismal Patterning, RIKEN Center for Developmental Biology, Kobe, Japan; 3Phyloinformatics Unit, RIKEN Center for Life Science Technologies, Kobe, Japan; 4Laboratory for Phyloinformatics, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan Abstract We have examined the role of Fam60a, a gene highly expressed in embryonic stem cells, in mouse development. Fam60a interacts with components of the Sin3a-Hdac transcriptional corepressor complex, and most Fam60a–/– embryos manifest hypoplasia of visceral organs and die in utero. Fam60a is recruited to the promoter regions of a subset of genes, with the expression of these genes being either up- or down-regulated in Fam60a–/– embryos. The DNA methylation level of the Fam60a target gene Adhfe1 is maintained at embryonic day (E) 7.5 but markedly reduced at –/– *For correspondence: E9.5 in Fam60a embryos, suggesting that DNA demethylation is enhanced in the mutant. [email protected] (SK); Examination of genome-wide DNA methylation identified several differentially methylated regions, [email protected] (HH) which were preferentially hypomethylated, in Fam60a–/– embryos. Our data suggest that Fam60a is †These authors contributed required for proper embryogenesis, at least in part as a result of its regulation of DNA methylation equally to this work at specific gene promoters. -
92324 ACTL6A/BAF53A (E3W2A) Rabbit Mab
Revision 1 C 0 2 - t ACTL6A/BAF53A (E3W2A) Rabbit a e r o t mAb S Orders: 877-616-CELL (2355) [email protected] 4 Support: 877-678-TECH (8324) 2 3 Web: [email protected] 2 www.cellsignal.com 9 # 3 Trask Lane Danvers Massachusetts 01923 USA For Research Use Only. Not For Use In Diagnostic Procedures. Applications: Reactivity: Sensitivity: MW (kDa): Source/Isotype: UniProt ID: Entrez-Gene Id: WB, IP, ChIP H Mk Endogenous 45 Rabbit IgG O96019 86 Product Usage Information Brg1/hBRM also plays a role as a tumor suppressor and Brg1 is mutated in several tumor cell lines (6-8). For optimal ChIP results, use 10 μl of antibody and 10 μg of chromatin (approximately 4 ACTL6/BAF53 proteins are highly homologous, actin-related proteins found in the × 106 cells) per IP. This antibody has been validated using SimpleChIP® Enzymatic SWI/SNF complex (9). In addition to the canonical SWI/SNF complex, ACT6LA/BAF53a Chromatin IP Kits. is also a member of the embryonic SWI/SNF complex, known as esBAF, which plays a role in pluripotency and development (10-12). ACTL6B/BAF53b is a member of the neural Application Dilution specific SWI/SNF complex and facilitates binding to target genes and is involved in memory and synaptic plasticity (13-15). ACTL6/BAF53 has been shown to interact with c- Western Blotting 1:1000 Myc, where it functions as a cofactor and is important in the transformation process (16). Immunoprecipitation 1:50 Further studies have shown ACTL6/BAF53 is associated with EMT and transformation in Chromatin IP 1:50 various cancers (17,18). -
Dynamic Landscape of Chromatin Accessibility and Transcriptomic
www.nature.com/scientificreports OPEN Dynamic landscape of chromatin accessibility and transcriptomic changes during diferentiation of human embryonic stem cells into dopaminergic neurons César Meléndez‑Ramírez1,2,6, Raquel Cuevas‑Diaz Duran3,6*, Tonatiuh Barrios‑García3, Mayela Giacoman‑Lozano3, Adolfo López‑Ornelas1,2,4, Jessica Herrera‑Gamboa3, Enrique Estudillo2, Ernesto Soto‑Reyes5, Iván Velasco1,2* & Víctor Treviño3* Chromatin architecture infuences transcription by modulating the physical access of regulatory factors to DNA, playing fundamental roles in cell identity. Studies on dopaminergic diferentiation have identifed coding genes, but the relationship with non‑coding genes or chromatin accessibility remains elusive. Using RNA‑Seq and ATAC‑Seq we profled diferentially expressed transcripts and open chromatin regions during early dopaminergic neuron diferentiation. Hierarchical clustering of diferentially expressed genes, resulted in 6 groups with unique characteristics. Surprisingly, the abundance of long non‑coding RNAs (lncRNAs) was high in the most downregulated transcripts, and depicted positive correlations with target mRNAs. We observed that open chromatin regions decrease upon diferentiation. Enrichment analyses of accessibility depict an association between open chromatin regions and specifc functional pathways and gene‑sets. A bioinformatic search for motifs allowed us to identify transcription factors and structural nuclear proteins that potentially regulate dopaminergic diferentiation. Interestingly, we also found changes in protein and mRNA abundance of the CCCTC‑binding factor, CTCF, which participates in genome organization and gene expression. Furthermore, assays demonstrated co‑localization of CTCF with Polycomb‑repressed chromatin marked by H3K27me3 in pluripotent cells, progressively decreasing in neural precursor cells and diferentiated neurons. Our work provides a unique resource of transcription factors and regulatory elements, potentially involved in the acquisition of human dopaminergic neuron cell identity.