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In Silico Prediction of High-Resolution Hi-C Interaction Matrices
ARTICLE https://doi.org/10.1038/s41467-019-13423-8 OPEN In silico prediction of high-resolution Hi-C interaction matrices Shilu Zhang1, Deborah Chasman 1, Sara Knaack1 & Sushmita Roy1,2* The three-dimensional (3D) organization of the genome plays an important role in gene regulation bringing distal sequence elements in 3D proximity to genes hundreds of kilobases away. Hi-C is a powerful genome-wide technique to study 3D genome organization. Owing to 1234567890():,; experimental costs, high resolution Hi-C datasets are limited to a few cell lines. Computa- tional prediction of Hi-C counts can offer a scalable and inexpensive approach to examine 3D genome organization across multiple cellular contexts. Here we present HiC-Reg, an approach to predict contact counts from one-dimensional regulatory signals. HiC-Reg pre- dictions identify topologically associating domains and significant interactions that are enri- ched for CCCTC-binding factor (CTCF) bidirectional motifs and interactions identified from complementary sources. CTCF and chromatin marks, especially repressive and elongation marks, are most important for HiC-Reg’s predictive performance. Taken together, HiC-Reg provides a powerful framework to generate high-resolution profiles of contact counts that can be used to study individual locus level interactions and higher-order organizational units of the genome. 1 Wisconsin Institute for Discovery, 330 North Orchard Street, Madison, WI 53715, USA. 2 Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53715, USA. *email: [email protected] NATURE COMMUNICATIONS | (2019) 10:5449 | https://doi.org/10.1038/s41467-019-13423-8 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-13423-8 he three-dimensional (3D) organization of the genome has Results Temerged as an important component of the gene regulation HiC-Reg for predicting contact count using Random Forests. -
NPRL3 Gene NPR3 Like, GATOR1 Complex Subunit
NPRL3 gene NPR3 like, GATOR1 complex subunit Normal Function The NPRL3 gene provides instructions for making a protein that is one piece of a group of proteins (complex) called GATOR1. This complex is found in cells throughout the body, where it regulates a signaling pathway called the mTOR pathway. The mTOR pathway is involved in cell growth and division (proliferation), the survival of cells, and the creation (synthesis) of new proteins. The role of the GATOR1 complex is to block this pathway by inhibiting (stopping) the activity of a complex called mTOR complex 1 ( mTORC1) that is integral to the mTOR pathway. In the brain, the mTOR pathway regulates many processes, including the growth and development of nerve cells and their ability to change and adapt over time (plasticity). Health Conditions Related to Genetic Changes Familial focal epilepsy with variable foci At least ten NPRL3 gene mutations have been found to cause familial focal epilepsy with variable foci (FFEVF), which is an uncommon form of recurrent seizures (epilepsy) that runs in families. Most of these mutations lead to the production of an abnormally short, nonfunctional protein. As a result, formation of normal GATOR1 complex is reduced, leading to overactivity of mTORC1 and excessive signaling of the mTOR pathway. It is not clear how an abnormally active mTOR pathway leads to the seizures of FFEVF. Research suggests that increased mTOR pathway signaling in the brain leads to changes in the connections between nerve cells (synapses) and increased activation (excitation) -
Mutational Inactivation of Mtorc1 Repressor Gene DEPDC5 in Human Gastrointestinal Stromal Tumors
Mutational inactivation of mTORC1 repressor gene DEPDC5 in human gastrointestinal stromal tumors Yuzhi Panga,1, Feifei Xiea,1, Hui Caob,1, Chunmeng Wangc,d,1, Meijun Zhue, Xiaoxiao Liua, Xiaojing Lua, Tao Huangf, Yanying Sheng,KeLia, Xiaona Jiaa, Zhang Lia, Xufen Zhenga, Simin Wanga,YiHeh, Linhui Wangi, Jonathan A. Fletchere,2, and Yuexiang Wanga,2 aKey Laboratory of Tissue Microenvironment and Tumor, Shanghai Institutes for Biological Sciences–Changzheng Hospital Joint Center for Translational Medicine, Changzheng Hospital, Institutes for Translational Medicine, Chinese Academy of Sciences–Second Military Medical University, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031 Shanghai, China; bDepartment of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127 Shanghai, China; cDepartment of Bone and Soft Tissue Sarcomas, Fudan University Shanghai Cancer Center, 200032 Shanghai, China; dDepartment of Oncology, Shanghai Medical College, Fudan University, 200032 Shanghai, China; eDepartment of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; fShanghai Information Center for Life Sciences, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China; gDepartment of Pathology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127 Shanghai, China; -
Repetitive Elements in Humans
International Journal of Molecular Sciences Review Repetitive Elements in Humans Thomas Liehr Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, D-07747 Jena, Germany; [email protected] Abstract: Repetitive DNA in humans is still widely considered to be meaningless, and variations within this part of the genome are generally considered to be harmless to the carrier. In contrast, for euchromatic variation, one becomes more careful in classifying inter-individual differences as meaningless and rather tends to see them as possible influencers of the so-called ‘genetic background’, being able to at least potentially influence disease susceptibilities. Here, the known ‘bad boys’ among repetitive DNAs are reviewed. Variable numbers of tandem repeats (VNTRs = micro- and minisatellites), small-scale repetitive elements (SSREs) and even chromosomal heteromorphisms (CHs) may therefore have direct or indirect influences on human diseases and susceptibilities. Summarizing this specific aspect here for the first time should contribute to stimulating more research on human repetitive DNA. It should also become clear that these kinds of studies must be done at all available levels of resolution, i.e., from the base pair to chromosomal level and, importantly, the epigenetic level, as well. Keywords: variable numbers of tandem repeats (VNTRs); microsatellites; minisatellites; small-scale repetitive elements (SSREs); chromosomal heteromorphisms (CHs); higher-order repeat (HOR); retroviral DNA 1. Introduction Citation: Liehr, T. Repetitive In humans, like in other higher species, the genome of one individual never looks 100% Elements in Humans. Int. J. Mol. Sci. alike to another one [1], even among those of the same gender or between monozygotic 2021, 22, 2072. -
Discovery of Novel Putative Tumor Suppressors from CRISPR Screens Reveals Rewired 2 Lipid Metabolism in AML Cells 3 4 W
bioRxiv preprint doi: https://doi.org/10.1101/2020.10.08.332023; this version posted August 20, 2021. 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 4.0 International license. 1 Discovery of novel putative tumor suppressors from CRISPR screens reveals rewired 2 lipid metabolism in AML cells 3 4 W. Frank Lenoir1,2, Micaela Morgado2, Peter C DeWeirdt3, Megan McLaughlin1,2, Audrey L 5 Griffith3, Annabel K Sangree3, Marissa N Feeley3, Nazanin Esmaeili Anvar1,2, Eiru Kim2, Lori L 6 Bertolet2, Medina Colic1,2, Merve Dede1,2, John G Doench3, Traver Hart2,4,* 7 8 9 1 - The University of Texas MD Anderson Cancer Center UTHealth Graduate School of 10 Biomedical Sciences; The University of Texas MD Anderson Cancer Center, Houston, TX 11 12 2 - Department of Bioinformatics and Computational Biology, The University of Texas MD 13 Anderson Cancer Center, Houston, TX, USA 14 15 3 - Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA 16 17 4 - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 18 Houston, TX, USA 19 20 21 22 23 * - Corresponding author: [email protected] 24 25 bioRxiv preprint doi: https://doi.org/10.1101/2020.10.08.332023; this version posted August 20, 2021. 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. -
Biology of Human Tumors Research Mir-409-3P/-5P Promotes Tumorigenesis, Epithelial-To-Mesenchymal Transition, and Bone Metastasis of Human Prostate Cancer
Published OnlineFirst June 24, 2014; DOI: 10.1158/1078-0432.CCR-14-0305 Clinical Cancer Biology of Human Tumors Research miR-409-3p/-5p Promotes Tumorigenesis, Epithelial-to-Mesenchymal Transition, and Bone Metastasis of Human Prostate Cancer Sajni Josson1, Murali Gururajan1, Peizhen Hu1, Chen Shao1, Gina Chia-Yi Chu1, Haiyen E. Zhau1, Chunyan Liu1, Kaiqin Lao2, Chia-Lun Lu1, Yi-Tsung Lu1, Jake Lichterman1, Srinivas Nandana1, Quanlin Li3, Andre Rogatko3, Dror Berel3, Edwin M. Posadas1, Ladan Fazli4, Dhruv Sareen5, and Leland W.K. Chung1 Abstract Purpose: miR-409-3p/-5p is a miRNA expressed by embryonic stem cells, and its role in cancer biology and metastasis is unknown. Our pilot studies demonstrated elevated miR-409-3p/-5p expression in humanprostatecancerbonemetastaticcelllines; therefore, we defined the biologic impact of manipulation of miR-409-3p/-5p on prostate cancer progression and correlated the levels of its expression with clinical human prostate cancer bone metastatic specimens. Experimental Design: miRNA profiling of a prostate cancer bone metastatic epithelial-to-mesenchymal transition (EMT) cell line model was performed. A Gleason score human tissue array was probed for validation of specific miRNAs. In addition, genetic manipulation of miR-409-3p/-5p was performed to determine its role in tumor growth, EMT, and bone metastasis in mouse models. Results: Elevated expression of miR-409-3p/-5p was observed in bone metastatic prostate cancer cell lines and human prostate cancer tissues with higher Gleason scores. Elevated miR-409-3p expression levels correlated with progression-free survival of patients with prostate cancer. Orthotopic delivery of miR-409- 3p/-5p in the murine prostate gland induced tumors where the tumors expressed EMT and stemness markers. -
Gene Ontology Functional Annotations and Pleiotropy
Network based analysis of genetic disease associations Sarah Gilman Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2013 Sarah Gilman All Rights Reserved ABSTRACT Network based analysis of genetic disease associations Sarah Gilman Despite extensive efforts and many promising early findings, genome-wide association studies have explained only a small fraction of the genetic factors contributing to common human diseases. There are many theories about where this “missing heritability” might lie, but increasingly the prevailing view is that common variants, the target of GWAS, are not solely responsible for susceptibility to common diseases and a substantial portion of human disease risk will be found among rare variants. Relatively new, such variants have not been subject to purifying selection, and therefore may be particularly pertinent for neuropsychiatric disorders and other diseases with greatly reduced fecundity. Recently, several researchers have made great progress towards uncovering the genetics behind autism and schizophrenia. By sequencing families, they have found hundreds of de novo variants occurring only in affected individuals, both large structural copy number variants and single nucleotide variants. Despite studying large cohorts there has been little recurrence among the genes implicated suggesting that many hundreds of genes may underlie these complex phenotypes. The question -
Functional Characterization of the Candidate Tumor Suppressor Gene NPRL2/G21 Located in 3P21.3C
[CANCER RESEARCH 64, 6438–6443, September 15, 2004] Functional Characterization of the Candidate Tumor Suppressor Gene NPRL2/G21 Located in 3p21.3C Jingfeng Li,1 Fuli Wang,1 Klas Haraldson,1 Alexey Protopopov,1 Fuh-Mei Duh,2,3 Laura Geil,2,3 Igor Kuzmin,2,3 John D. Minna,4 Eric Stanbridge,5 Eleonora Braga,6 Vladimir I. Kashuba,1,7 George Klein,1 Michael I. Lerman,2 and Eugene R. Zabarovsky1,8 1Microbiology and Tumor Biology Center, Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden; 2Cancer-Causing Genes Section, Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland; 3Basic Research Program, SAIC-Frederick, Inc., Frederick, Maryland; 4Hamon Center for Therapeutic Oncology, Research, University of Texas Southwestern Medical Center, Dallas, Texas; 5Department of Microbiology and Molecular Genetics, College of Medicine, University of California at Irvine, Irvine, California; 6Russian State Genetics Center, Moscow, Russia; 7Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kiev, Ukraine; and 8Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia ABSTRACT accompanied by chromosome 3p homozygous deletions, is a charac- teristic feature of most major epithelial carcinomas, such as lung, Initial analysis identified the NPRL2/G21 gene located in 3p21.3C, the breast, cervical, oral cavity, ovary, and kidney (2, 3). These changes lung cancer region, as a strong candidate tumor suppressor gene. Here we indicate the involvement of multiple tumor suppressor genes. provide additional evidence of the tumor suppressor function of NPRL2/ G21. The gene has highly conserved homologs/orthologs ranging from We have performed a comprehensive deletion survey of 3p on more yeast to humans. -
Genomic Diagnostics Within a Medically Underserved Population: Efficacy and Implications
© American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Genomic diagnostics within a medically underserved population: efficacy and implications Kevin A. Strauss, MD1, Claudia Gonzaga-Jauregui, PhD2, Karlla W. Brigatti, MS1, Katie B. Williams, MD, PhD1, Alejandra K. King, PhD2, Cristopher Van Hout, PhD2, Donna L. Robinson, CRNP1, Millie Young, RNC1, Kavita Praveen, PhD2, Adam D. Heaps, MS1, Mindy Kuebler, MS1, Aris Baras, MD2, Jeffrey G. Reid, PhD2, John D. Overton, PhD2, Frederick E. Dewey, MD2, Robert N. Jinks, PhD3, Ian Finnegan, BA3, Scott J. Mellis, MD, PhD2, Alan R. Shuldiner, MD2 and Erik G. Puffenberger, PhD1 Purpose: We integrated whole-exome sequencing (WES) and Compared to trio analysis, “family” WES (average seven exomes chromosomal microarray analysis (CMA) into a clinical workflow per proband) reduced filtered candidate variants from 22 ± 6to to serve an endogamous, uninsured, agrarian community. 5 ± 3 per proband. Nineteen (51%) alleles were de novo and 17 Methods: Seventy-nine probands (newborn to 49.8 years) who (46%) inherited; the latter added to a population-based diagnostic presented between 1998 and 2015 remained undiagnosed after panel. We found actionable secondary variants in 21 (4.2%) of 502 biochemical and molecular investigations. We generated WES data subjects, all of whom opted to be informed. for probands and family members and vetted variants through Conclusion: CMA and family-based WES streamline and rephenotyping, segregation analyses, and population studies. economize diagnosis of rare genetic disorders, accelerate novel Results: The most common presentation was neurological disease gene discovery, and create new opportunities for community-based (64%). Seven (9%) probands were diagnosed by CMA. -
Concordance of Copy Number Loss and Down-Regulation of Tumor Suppressor Genes: a Pan-Cancer Study Min Zhao1 and Zhongming Zhao2,3,4,5*
The Author(s) BMC Genomics 2016, 17(Suppl 7):532 DOI 10.1186/s12864-016-2904-y RESEARCH Open Access Concordance of copy number loss and down-regulation of tumor suppressor genes: a pan-cancer study Min Zhao1 and Zhongming Zhao2,3,4,5* From The International Conference on Intelligent Biology and Medicine (ICIBM) 2015 Indianapolis, IN, USA. 13-15 November 2015 Abstract Background: Tumor suppressor genes (TSGs) encode the guardian molecules to control cell growth. The genomic alteration of TSGs may cause tumorigenesis and promote cancer progression. So far, investigators have mainly studied the functional effects of somatic single nucleotide variants in TSGs. Copy number variation (CNV) is another important form of genetic variation, and is often involved in cancer biology and drug treatment, but studies of CNV in TSGs are less represented in literature. In addition, there is a lack of a combinatory analysis of gene expression and CNV in this important gene set. Such a study may provide more insights into the relationship between gene dosage and tumorigenesis. To meet this demand, we performed a systematic analysis of CNVs and gene expression in TSGs to provide a systematic view of CNV and gene expression change in TSGs in pan-cancer. Results: We identified 1170 TSGs with copy number gain or loss in 5846 tumor samples. Among them, 207 TSGs tended to have copy number loss (CNL), from which fifteen CNL hotspot regions were identified. The functional enrichment analysis revealed that the 207 TSGs were enriched in cancer-related pathways such as P53 signaling pathway and the P53 interactome. -
Nprl3 Gene Intron That Enhances Its Transcription in Peripheral Blood
Scuola Internazionale Superiore di Studi Avanzati PhD Course in Functional and Structural Genomics Discovery of a human VNTR allelic variant in Nprl3 gene intron that enhances its transcription in peripheral blood Thesis submitted for the degree of “Philosophiæ Doctor” Candidate Supervisor Maria Bertuzzi Prof. Stefano Gustincich Academic Year 2014-2015 Table of contents Table of contents Abstract ....................................................................................................................................1 Introduction ..............................................................................................................................3 Gene expression regulation ..................................................................................................3 Gene expression profiling ................................................................................................5 NanoCAGE ......................................................................................................................6 TSS complexity ................................................................................................................7 Expression Quantitative Trait Loci (eQTL) .....................................................................8 Repetitive elements in the mammalian genome.................................................................10 Minisatellites and human diseases .................................................................................11 Parkinson’s disease.............................................................................................................14 -
NPRL3 (L-20): Sc-242062
SAN TA C RUZ BI OTEC HNOL OG Y, INC . NPRL3 (L-20): sc-242062 BACKGROUND PRODUCT NPRL3 (nitrogen permease regulator 3-like protein), also known as CGTHBA Each vial contains 200 µg IgG in 1.0 ml of PBS with < 0.1% sodium azide (conserved gene telomeric to α globin cluster), MARE, NPR3 or RMD11, is a and 0.1% gelatin. 569 amino acid protein that belongs to the NPR3 family. NPRL3 is widely ex- Blocking peptide available for competition studies, sc-242062 P, (100 µg pressed and forms a heterodimer with NPRL2. The gene that encodes NPRL3 peptide in 0.5 ml PBS containing < 0.1% sodium azide and 0.2% BSA). consists of approximately 54,587 bases and maps to human chromosome 16p13.3. Encoding over 900 genes and consisting of approximately 90 mil lion APPLICATIONS base pairs, chromosome 16 makes up nearly 3% of the human genome and is associated with a variety of genetic disorders. The GAN gene is located on NPRL3 (L-20) is recommended for detection of NPRL3 of mouse, rat and chromosome 16 and, when mutated, may lead to giant axonal neuropathy, a human origin by Western Blotting (starting dilution 1:200, dilution range nervous system disorder characterized by increasing malfunction with growth. 1:100-1:1000), immunofluorescence (starting dilution 1:50, dilution range Alterations in the CREB gene and NOD2 gene, both of which are located on 1:50-1:500) and solid phase ELISA (starting dilution 1:30, dilution range chromosome 16, results in Rubinstein-Taybi syndrome and Crohn’s disease, 1:30-1:3000).