The Male Germ Cell Gene Regulator CTCFL Is Functionally Different from CTCF and Binds CTCF-Like Consensus Sites in a Nucleosome Composition-Dependent Manner
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Expression of the POTE Gene Family in Human Ovarian Cancer Carter J Barger1,2, Wa Zhang1,2, Ashok Sharma 1,2, Linda Chee1,2, Smitha R
www.nature.com/scientificreports OPEN Expression of the POTE gene family in human ovarian cancer Carter J Barger1,2, Wa Zhang1,2, Ashok Sharma 1,2, Linda Chee1,2, Smitha R. James3, Christina N. Kufel3, Austin Miller 4, Jane Meza5, Ronny Drapkin 6, Kunle Odunsi7,8,9, 2,10 1,2,3 Received: 5 July 2018 David Klinkebiel & Adam R. Karpf Accepted: 7 November 2018 The POTE family includes 14 genes in three phylogenetic groups. We determined POTE mRNA Published: xx xx xxxx expression in normal tissues, epithelial ovarian and high-grade serous ovarian cancer (EOC, HGSC), and pan-cancer, and determined the relationship of POTE expression to ovarian cancer clinicopathology. Groups 1 & 2 POTEs showed testis-specifc expression in normal tissues, consistent with assignment as cancer-testis antigens (CTAs), while Group 3 POTEs were expressed in several normal tissues, indicating they are not CTAs. Pan-POTE and individual POTEs showed signifcantly elevated expression in EOC and HGSC compared to normal controls. Pan-POTE correlated with increased stage, grade, and the HGSC subtype. Select individual POTEs showed increased expression in recurrent HGSC, and POTEE specifcally associated with reduced HGSC OS. Consistent with tumors, EOC cell lines had signifcantly elevated Pan-POTE compared to OSE and FTE cells. Notably, Group 1 & 2 POTEs (POTEs A/B/B2/C/D), Group 3 POTE-actin genes (POTEs E/F/I/J/KP), and other Group 3 POTEs (POTEs G/H/M) show within-group correlated expression, and pan-cancer analyses of tumors and cell lines confrmed this relationship. Based on their restricted expression in normal tissues and increased expression and association with poor prognosis in ovarian cancer, POTEs are potential oncogenes and therapeutic targets in this malignancy. -
The Cancer-Associated CTCFL/BORIS Protein Targets Multiple Classes of Genomic Repeats, with a Distinct Binding and Functional Pr
Pugacheva et al. Epigenetics & Chromatin (2016) 9:35 DOI 10.1186/s13072-016-0084-2 Epigenetics & Chromatin RESEARCH Open Access The cancer‑associated CTCFL/BORIS protein targets multiple classes of genomic repeats, with a distinct binding and functional preference for humanoid‑specific SVA transposable elements Elena M. Pugacheva2, Evgeny Teplyakov1, Qiongfang Wu1, Jingjing Li1, Cheng Chen1, Chengcheng Meng1, Jian Liu1, Susan Robinson2, Dmitry Loukinov2, Abdelhalim Boukaba1, Andrew Paul Hutchins3, Victor Lobanenkov2 and Alexander Strunnikov1* Abstract Background: A common aberration in cancer is the activation of germline-specific proteins. The DNA-binding pro- teins among them could generate novel chromatin states, not found in normal cells. The germline-specific transcrip- tion factor BORIS/CTCFL, a paralog of chromatin architecture protein CTCF, is often erroneously activated in cancers and rewires the epigenome for the germline-like transcription program. Another common feature of malignancies is the changed expression and epigenetic states of genomic repeats, which could alter the transcription of neighboring genes and cause somatic mutations upon transposition. The role of BORIS in transposable elements and other repeats has never been assessed. Results: The investigation of BORIS and CTCF binding to DNA repeats in the K562 cancer cells dependent on BORIS for self-renewal by ChIP-chip and ChIP-seq revealed three classes of occupancy by these proteins: elements cohabited by BORIS and CTCF, CTCF-only bound, or BORIS-only bound. The CTCF-only enrichment is characteristic for evolu- tionary old and inactive repeat classes, while BORIS and CTCF co-binding predominately occurs at uncharacterized tandem repeats. These repeats form staggered cluster binding sites, which are a prerequisite for CTCF and BORIS co-binding. -
Molecular Architecture of CTCFL
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochemical and Biophysical Research Communications 396 (2010) 648–650 Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc Molecular architecture of CTCFL Amy E. Campbell 1, Selena R. Martinez, JJ L. Miranda * Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA article info abstract Article history: The CTCF-like protein, CTCFL, is a DNA-binding factor that regulates the transcriptional program of mam- Received 16 April 2010 malian male germ cells. CTCFL consists of eleven zinc fingers flanked by polypeptides of unknown struc- Available online 8 May 2010 ture and function. We determined that the C-terminal fragment predominantly consists of extended and unordered content. Computational analysis predicts that the N-terminal segment is also disordered. The Keywords: molecular architecture of CTCFL may then be similar to that of its paralog, the CCCTC-binding factor, CTCFL CTCF. We speculate that sequence divergence in the unstructured terminal segments results in differen- Chromatin tial recruitment of cofactors, perhaps defining the functional distinction between CTCF in somatic cells Transcription and CTCFL in the male germ line. Insulator CTCF Ó 2010 Elsevier Inc. Open access under CC BY-NC-ND license. 1. Introduction Computational analysis predicts that the N-terminal segment may be disordered as well. We discuss the functional implications The CTCF-like protein, referred to as CTCFL or BORIS, regulates of a similar structural architecture on the functional differences be- transcription in the human male germ line. -
CORVET, CHEVI and HOPS – Multisubunit Tethers of the Endo
© 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs189134. doi:10.1242/jcs.189134 REVIEW SUBJECT COLLECTION: CELL BIOLOGY AND DISEASE CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease Jan van der Beek‡, Caspar Jonker*,‡, Reini van der Welle, Nalan Liv and Judith Klumperman§ ABSTRACT contact between two opposing membranes and pull them close Multisubunit tethering complexes (MTCs) are multitasking hubs that together to allow interactions between SNARE proteins (Murray form a link between membrane fusion, organelle motility and signaling. et al., 2016). SNARE assembly then provides additional fusion CORVET, CHEVI and HOPS are MTCs of the endo-lysosomal system. specificity and drives the actual fusion process (Ohya et al., 2009; They regulate the major membrane flows required for endocytosis, Stroupe et al., 2009). In this Review, we focus on the role of tethering lysosome biogenesis, autophagy and phagocytosis. In addition, proteins in endo-lysosomal fusion events. individual subunits control complex-independent transport of specific Tethering proteins can be divided into two main groups: long cargoes and exert functions beyond tethering, such as attachment to coiled-coil proteins (Gillingham and Munro, 2003) and microtubules and SNARE activation. Mutations in CHEVI subunits multisubunit tethering complexes (MTCs). MTCs form a lead to arthrogryposis, renal dysfunction and cholestasis (ARC) heterogenic group of protein complexes that consist of up to ten ∼ syndrome, while defects in CORVET and, particularly, HOPS are subunits resulting in a general length of 50 nm (Brocker et al., associated with neurodegeneration, pigmentation disorders, liver 2012; Chou et al., 2016; Hsu et al., 1998; Lürick et al., 2018; Ren malfunction and various forms of cancer. -
Organ of Corti Size Is Governed by Yap/Tead-Mediated Progenitor Self-Renewal
Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal Ksenia Gnedevaa,b,1, Xizi Wanga,b, Melissa M. McGovernc, Matthew Bartond,2, Litao Taoa,b, Talon Treceka,b, Tanner O. Monroee,f, Juan Llamasa,b, Welly Makmuraa,b, James F. Martinf,g,h, Andrew K. Grovesc,g,i, Mark Warchold, and Neil Segila,b,1 aDepartment of Stem Cell Biology and Regenerative Medicine, Keck Medicine of University of Southern California, Los Angeles, CA 90033; bCaruso Department of Otolaryngology–Head and Neck Surgery, Keck Medicine of University of Southern California, Los Angeles, CA 90033; cDepartment of Neuroscience, Baylor College of Medicine, Houston, TX 77030; dDepartment of Otolaryngology, Washington University in St. Louis, St. Louis, MO 63130; eAdvanced Center for Translational and Genetic Medicine, Lurie Children’s Hospital of Chicago, Chicago, IL 60611; fDepartment of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030; gProgram in Developmental Biology, Baylor College of Medicine, Houston, TX 77030; hCardiomyocyte Renewal Laboratory, Texas Heart Institute, Houston, TX 77030 and iDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; Edited by Marianne E. Bronner, California Institute of Technology, Pasadena, CA, and approved April 21, 2020 (received for review January 6, 2020) Precise control of organ growth and patterning is executed However, what initiates this increase in Cdkn1b expression re- through a balanced regulation of progenitor self-renewal and dif- mains unclear. In addition, conditional ablation of Cdkn1b in the ferentiation. In the auditory sensory epithelium—the organ of inner ear is not sufficient to completely relieve the block on Corti—progenitor cells exit the cell cycle in a coordinated wave supporting cell proliferation (9, 10), suggesting the existence of between E12.5 and E14.5 before the initiation of sensory receptor additional repressive mechanisms. -
(PAD) and Post-Translational Protein Deimination—Novel Insights Into Alveolata Metabolism, Epigenetic Regulation and Host–Pathogen Interactions
biology Article Peptidylarginine Deiminase (PAD) and Post-Translational Protein Deimination—Novel Insights into Alveolata Metabolism, Epigenetic Regulation and Host–Pathogen Interactions Árni Kristmundsson 1,*, Ásthildur Erlingsdóttir 1 and Sigrun Lange 2,* 1 Institute for Experimental Pathology at Keldur, University of Iceland, Keldnavegur 3, 112 Reykjavik, Iceland; [email protected] 2 Tissue Architecture and Regeneration Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK * Correspondence: [email protected] (Á.K.); [email protected] (S.L.) Simple Summary: Alveolates are a major group of free living and parasitic organisms; some of which are serious pathogens of animals and humans. Apicomplexans and chromerids are two phyla belonging to the alveolates. Apicomplexans are obligate intracellular parasites; that cannot complete their life cycle without exploiting a suitable host. Chromerids are mostly photoautotrophs as they can obtain energy from sunlight; and are considered ancestors of the apicomplexans. The pathogenicity and life cycle strategies differ significantly between parasitic alveolates; with some causing major losses in host populations while others seem harmless to the host. As the life cycles of Citation: Kristmundsson, Á.; Erlingsdóttir, Á.; Lange, S. some are still poorly understood, a better understanding of the factors which can affect the parasitic Peptidylarginine Deiminase (PAD) alveolates’ life cycles and survival is of great importance and may aid in new biomarker discovery. and Post-Translational Protein This study assessed new mechanisms relating to changes in protein structure and function (so-called Deimination—Novel Insights into “deimination” or “citrullination”) in two key parasites—an apicomplexan and a chromerid—to Alveolata Metabolism, Epigenetic assess the pathways affected by this protein modification. -
Genomic and Expression Profiling of Human Spermatocytic Seminomas: Primary Spermatocyte As Tumorigenic Precursor and DMRT1 As Candidate Chromosome 9 Gene
Research Article Genomic and Expression Profiling of Human Spermatocytic Seminomas: Primary Spermatocyte as Tumorigenic Precursor and DMRT1 as Candidate Chromosome 9 Gene Leendert H.J. Looijenga,1 Remko Hersmus,1 Ad J.M. Gillis,1 Rolph Pfundt,4 Hans J. Stoop,1 Ruud J.H.L.M. van Gurp,1 Joris Veltman,1 H. Berna Beverloo,2 Ellen van Drunen,2 Ad Geurts van Kessel,4 Renee Reijo Pera,5 Dominik T. Schneider,6 Brenda Summersgill,7 Janet Shipley,7 Alan McIntyre,7 Peter van der Spek,3 Eric Schoenmakers,4 and J. Wolter Oosterhuis1 1Department of Pathology, Josephine Nefkens Institute; Departments of 2Clinical Genetics and 3Bioinformatics, Erasmus Medical Center/ University Medical Center, Rotterdam, the Netherlands; 4Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; 5Howard Hughes Medical Institute, Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; 6Clinic of Paediatric Oncology, Haematology and Immunology, Heinrich-Heine University, Du¨sseldorf, Germany; 7Molecular Cytogenetics, Section of Molecular Carcinogenesis, The Institute of Cancer Research, Sutton, Surrey, United Kingdom Abstract histochemistry, DMRT1 (a male-specific transcriptional regulator) was identified as a likely candidate gene for Spermatocytic seminomas are solid tumors found solely in the involvement in the development of spermatocytic seminomas. testis of predominantly elderly individuals. We investigated these tumors using a genome-wide analysis for structural and (Cancer Res 2006; 66(1): 290-302) numerical chromosomal changes through conventional kar- yotyping, spectral karyotyping, and array comparative Introduction genomic hybridization using a 32 K genomic tiling-path Spermatocytic seminomas are benign testicular tumors that resolution BAC platform (confirmed by in situ hybridization). -
The DNA Sequence and Comparative Analysis of Human Chromosome 20
articles The DNA sequence and comparative analysis of human chromosome 20 P. Deloukas, L. H. Matthews, J. Ashurst, J. Burton, J. G. R. Gilbert, M. Jones, G. Stavrides, J. P. Almeida, A. K. Babbage, C. L. Bagguley, J. Bailey, K. F. Barlow, K. N. Bates, L. M. Beard, D. M. Beare, O. P. Beasley, C. P. Bird, S. E. Blakey, A. M. Bridgeman, A. J. Brown, D. Buck, W. Burrill, A. P. Butler, C. Carder, N. P. Carter, J. C. Chapman, M. Clamp, G. Clark, L. N. Clark, S. Y. Clark, C. M. Clee, S. Clegg, V. E. Cobley, R. E. Collier, R. Connor, N. R. Corby, A. Coulson, G. J. Coville, R. Deadman, P. Dhami, M. Dunn, A. G. Ellington, J. A. Frankland, A. Fraser, L. French, P. Garner, D. V. Grafham, C. Grif®ths, M. N. D. Grif®ths, R. Gwilliam, R. E. Hall, S. Hammond, J. L. Harley, P. D. Heath, S. Ho, J. L. Holden, P. J. Howden, E. Huckle, A. R. Hunt, S. E. Hunt, K. Jekosch, C. M. Johnson, D. Johnson, M. P. Kay, A. M. Kimberley, A. King, A. Knights, G. K. Laird, S. Lawlor, M. H. Lehvaslaiho, M. Leversha, C. Lloyd, D. M. Lloyd, J. D. Lovell, V. L. Marsh, S. L. Martin, L. J. McConnachie, K. McLay, A. A. McMurray, S. Milne, D. Mistry, M. J. F. Moore, J. C. Mullikin, T. Nickerson, K. Oliver, A. Parker, R. Patel, T. A. V. Pearce, A. I. Peck, B. J. C. T. Phillimore, S. R. Prathalingam, R. W. Plumb, H. Ramsay, C. M. -
The Diverging Routes of BORIS and CTCF: an Interactomic and Phylogenomic Analysis
life Article The Diverging Routes of BORIS and CTCF: An Interactomic and Phylogenomic Analysis Kamel Jabbari * ID , Peter Heger, Ranu Sharma and Thomas Wiehe ID Cologne Biocenter, Institute for Genetics, University of Cologne, Zülpicher Straße 47a, 50674 Köln, Germany; [email protected] (P.H.); [email protected] (R.S.); [email protected] (T.W.) * Correspondence: [email protected]; Tel.: +49-221-470-1586 Received: 23 December 2017; Accepted: 25 January 2018; Published: 30 January 2018 Abstract: The CCCTC-binding factor (CTCF) is multi-functional, ubiquitously expressed, and highly conserved from Drosophila to human. It has important roles in transcriptional insulation and the formation of a high-dimensional chromatin structure. CTCF has a paralog called “Brother of Regulator of Imprinted Sites” (BORIS) or “CTCF-like” (CTCFL). It binds DNA at sites similar to those of CTCF. However, the expression profiles of the two proteins are quite different. We investigated the evolutionary trajectories of the two proteins after the duplication event using a phylogenomic and interactomic approach. We find that CTCF has 52 direct interaction partners while CTCFL only has 19. Almost all interactors already existed before the emergence of CTCF and CTCFL. The unique secondary loss of CTCF from several nematodes is paralleled by a loss of two of its interactors, the polycomb repressive complex subunit SuZ12 and the multifunctional transcription factor TYY1. In contrast to earlier studies reporting the absence of BORIS from birds, we present evidence for a multigene synteny block containing CTCFL that is conserved in mammals, reptiles, and several species of birds, indicating that not the entire lineage of birds experienced a loss of CTCFL. -
(Bag3) and Its P209L Mutant
Characterization and interaction studies of Bcl-2-associated athanogene 3 (Bag3) and its P209L mutant Jeffrey Li Department of Biochemistry McGill University, Montreal August 2018 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Master of Science © Jeffrey Li 2018 1 Abstract: A genetic form of myofibrillar myopathy (MFM) has been linked to a P209L mutation in Bag3, with patients exhibiting childhood-onset progressive skeletal muscle weakness and associated cardiomyopathy. Microscopy studies on MFM patients show myofibril disintegration beginning at the Z-disk and formation of protein aggregates. Bag3 is a member of the BAG family of Hsp70 nucleotide exchange factors, and is associated with a number of pathways, such as selective autophagy, aggresome formation and Hippo pathway regulation. Previous work in zebrafish suggests Bag3-P209L is aggregation-prone and can sequester wildtype Bag3 into aggregates, leading to a loss of Bag3 function. How a loss in Bag3 function leads to the disease is unknown. We identified changes in Bag3 phosphorylation at residues linked to regulation of the heat shock response. BioID comparison of wildtype Bag3 and Bag3-P209L interactors in the soluble and insoluble fraction show potential changes in pathways such as autophagy, Hippo and Wnt pathway regulation, signal transduction, and actin cytoskeleton maintenance. Interestingly, a Bag3 function in Wnt signaling has never been reported. With these findings, we propose several hypotheses describing how the observed gain and loss of interaction caused by the P209L mutation may affect Bag3-associated pathways, and how these aberrancies could contribute to the MFM phenotype. 2 Résumé: Une forme génétique de la myopathie myofibrillaire (MMF) a été liée à une mutation P209L dans la protéine Bag3. -
Identifying Loci Under Positive Selection in Complex Population Histories
bioRxiv preprint doi: https://doi.org/10.1101/453092; this version posted October 25, 2018. 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 4.0 International license. Identifying loci under positive selection in complex population histories Alba Refoyo-Martínez1, Rute R. da Fonseca2, Katrín Halldórsdóttir3, Einar Árnason3;4, Thomas Mailund5, Fernando Racimo1;∗ 1 Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Denmark. 2 Centre for Macroecology, Evolution and Climate, Natural History Museum of Denmark, University of Copenhagen, Denmark. 3 Institute of Life and Environmental Sciences, University of Iceland, Reykjavík, Iceland. 4 Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, USA. 5 Bioinformatics Research Centre, Aarhus University, Denmark. * Corresponding author: [email protected] October 25, 2018 Abstract Detailed modeling of a species’ history is of prime importance for understanding how natural selection operates over time. Most methods designed to detect positive selection along sequenced genomes, however, use simplified representations of past histories as null models of genetic drift. Here, we present the first method that can detect signatures of strong local adaptation across the genome using arbitrarily complex admixture graphs, which are typically used to describe the history of past divergence and admixture events among any number of populations. The method—called Graph-aware Retrieval of Selective Sweeps (GRoSS)—has good power to detect loci in the genome with strong evidence for past selective sweeps and can also identify which branch of the graph was most affected by the sweep. -
HOPS-Dependent Endosomal Fusion Required for Efficient Cytosolic Delivery of Therapeutic Peptides and Small Proteins
HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins Angela Steinauera, Jonathan R. LaRochelleb, Susan L. Knoxa, Rebecca F. Wissnera, Samuel Berryc, and Alanna Schepartza,b,1 aDepartment of Chemistry, Yale University, New Haven, CT 06520-8107; bDepartment of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520-8103; and cDepartment of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114 Edited by James A. Wells, University of California, San Francisco, CA, and approved November 26, 2018 (received for review July 17, 2018) Protein therapeutics represent a significant and growing compo- Recently, we discovered that, when added to cells, certain small, nent of the modern pharmacopeia, but their potential to treat folded miniature proteins (9, 10) derived from avian pancreatic human disease is limited because most proteins fail to traffic polypeptide (aPP) or an isolated zinc-finger (ZF) domain, are across biological membranes. Recently, we discovered a class of taken up into the endocytic pathway and subsequently released cell-permeant miniature proteins (CPMPs) containing a precisely into the cytosol with unprecedented efficiencies (11, 12). The most defined, penta-arginine (penta-Arg) motif that traffics readily to effective molecules are defined by a discrete array of five arginine the cytosol and nucleus of mammalian cells with efficiencies that residues on a folded α-helix (13); we refer to these molecules as rival those of hydrocarbon-stapled peptides active in animals and cell-permeant miniature proteins (CPMPs). Treatment of HeLa man. Like many cell-penetrating peptides (CPPs), CPMPs enter the cells in culture with the CPMP ZF5.3 leads to a ZF5.3 concen- endocytic pathway; the difference is that CPMPs containing a penta- tration in the cytosol that is roughly 67% of the extracellular in- Arg motif are released efficiently from endosomes, while other CPPs cubation concentration; this value is at least 10-fold higher than are not.