Long Noncoding Rnas in Organogenesis
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Regulation of Cardiac Progenitors by Combination of Mesp1 and ETS
REGULATION OF CARDIAC PROGENITORS BY COMBINATION OF MESP1 AND ETS TRANSCRIPTION FACTORS A Dissertation by KUO-CHAN WENG Submitted to the Office of Graduate and Professional Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee, Fen Wang Co-Chair of Committee, Robert J. Schwartz Committee Members, James F. Martin Jiang Chang Head of Department, Fen Wang May 2014 Major Subject: Medical Science Copyright 2014 Kuo-Chan Weng ABSTRACT Heart disease remains the leading cause of death worldwide. By understanding the regulating networks during cardiac development we can exploit those networks to manipulate adult cells into cardiac progenitors and provide an alternative for repairing diseased hearts. Mesp1 is considered to have critical roles during cardiac development but the molecular mechanisms need to be further studied. The roles of ETS transcription factors have been primarily limited to hematopoietic differentiation and cancer progression. The ETS transcription factors are known to have proliferating roles and were hypothesized to also be involved in cardiac differentiation and may potentially be used for cell reprogramming. The first part of this study characterizes the expression pattern of Mesp1 protein in early mouse embryo from E6.5 to E9.5 and provides a full expression profile in differentiating embryoid bodies in vitro from the undifferentiated stage to Day10. Our work showed Mesp1 expresses in the posterior region of E6.5 embryo then starts migrating through the primitive streak toward anterior mesoderm and endoderm in E7.5. A Mesp1 linage tracing ES cell line was established, and it allowed us to trace the Mesp1 derived cell population. -
Detailed Review Paper on Retinoid Pathway Signalling
1 1 Detailed Review Paper on Retinoid Pathway Signalling 2 December 2020 3 2 4 Foreword 5 1. Project 4.97 to develop a Detailed Review Paper (DRP) on the Retinoid System 6 was added to the Test Guidelines Programme work plan in 2015. The project was 7 originally proposed by Sweden and the European Commission later joined the project as 8 a co-lead. In 2019, the OECD Secretariat was added to coordinate input from expert 9 consultants. The initial objectives of the project were to: 10 draft a review of the biology of retinoid signalling pathway, 11 describe retinoid-mediated effects on various organ systems, 12 identify relevant retinoid in vitro and ex vivo assays that measure mechanistic 13 effects of chemicals for development, and 14 Identify in vivo endpoints that could be added to existing test guidelines to 15 identify chemical effects on retinoid pathway signalling. 16 2. This DRP is intended to expand the recommendations for the retinoid pathway 17 included in the OECD Detailed Review Paper on the State of the Science on Novel In 18 vitro and In vivo Screening and Testing Methods and Endpoints for Evaluating 19 Endocrine Disruptors (DRP No 178). The retinoid signalling pathway was one of seven 20 endocrine pathways considered to be susceptible to environmental endocrine disruption 21 and for which relevant endpoints could be measured in new or existing OECD Test 22 Guidelines for evaluating endocrine disruption. Due to the complexity of retinoid 23 signalling across multiple organ systems, this effort was foreseen as a multi-step process. -
Table 2. Significant
Table 2. Significant (Q < 0.05 and |d | > 0.5) transcripts from the meta-analysis Gene Chr Mb Gene Name Affy ProbeSet cDNA_IDs d HAP/LAP d HAP/LAP d d IS Average d Ztest P values Q-value Symbol ID (study #5) 1 2 STS B2m 2 122 beta-2 microglobulin 1452428_a_at AI848245 1.75334941 4 3.2 4 3.2316485 1.07398E-09 5.69E-08 Man2b1 8 84.4 mannosidase 2, alpha B1 1416340_a_at H4049B01 3.75722111 3.87309653 2.1 1.6 2.84852656 5.32443E-07 1.58E-05 1110032A03Rik 9 50.9 RIKEN cDNA 1110032A03 gene 1417211_a_at H4035E05 4 1.66015788 4 1.7 2.82772795 2.94266E-05 0.000527 NA 9 48.5 --- 1456111_at 3.43701477 1.85785922 4 2 2.8237185 9.97969E-08 3.48E-06 Scn4b 9 45.3 Sodium channel, type IV, beta 1434008_at AI844796 3.79536664 1.63774235 3.3 2.3 2.75319499 1.48057E-08 6.21E-07 polypeptide Gadd45gip1 8 84.1 RIKEN cDNA 2310040G17 gene 1417619_at 4 3.38875643 1.4 2 2.69163229 8.84279E-06 0.0001904 BC056474 15 12.1 Mus musculus cDNA clone 1424117_at H3030A06 3.95752801 2.42838452 1.9 2.2 2.62132809 1.3344E-08 5.66E-07 MGC:67360 IMAGE:6823629, complete cds NA 4 153 guanine nucleotide binding protein, 1454696_at -3.46081884 -4 -1.3 -1.6 -2.6026947 8.58458E-05 0.0012617 beta 1 Gnb1 4 153 guanine nucleotide binding protein, 1417432_a_at H3094D02 -3.13334396 -4 -1.6 -1.7 -2.5946297 1.04542E-05 0.0002202 beta 1 Gadd45gip1 8 84.1 RAD23a homolog (S. -
Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin
cells Review Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin Agnieszka Bochy ´nska,Juliane Lüscher-Firzlaff and Bernhard Lüscher * ID Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen, Germany; [email protected] (A.B.); jluescher-fi[email protected] (J.L.-F.) * Correspondence: [email protected]; Tel.: +49-241-8088850; Fax: +49-241-8082427 Received: 18 January 2018; Accepted: 27 February 2018; Published: 2 March 2018 Abstract: Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is the control of specific properties of nucleosomes, the basic units of chromatin, and their protein components, the core histones. The main principles are to regulate the position and the characteristics of nucleosomes. The latter includes modulating the composition of core histones and their variants that are integrated into nucleosomes, and the post-translational modification of these histones referred to as histone marks. One of these marks is the methylation of lysine 4 of the core histone H3 (H3K4). While mono-methylation of H3K4 (H3K4me1) is located preferentially at active enhancers, tri-methylation (H3K4me3) is a mark found at open and potentially active promoters. Thus, H3K4 methylation is typically associated with gene transcription. The class 2 lysine methyltransferases (KMTs) are the main enzymes that methylate H3K4. KMT2 enzymes function in complexes that contain a necessary core complex composed of WDR5, RBBP5, ASH2L, and DPY30, the so-called WRAD complex. -
Watsonjn2018.Pdf (1.780Mb)
UNIVERSITY OF CENTRAL OKLAHOMA Edmond, Oklahoma Department of Biology Investigating Differential Gene Expression in vivo of Cardiac Birth Defects in an Avian Model of Maternal Phenylketonuria A THESIS SUBMITTED TO THE GRADUATE FACULTY In partial fulfillment of the requirements For the degree of MASTER OF SCIENCE IN BIOLOGY By Jamie N. Watson Edmond, OK June 5, 2018 J. Watson/Dr. Nikki Seagraves ii J. Watson/Dr. Nikki Seagraves Acknowledgements It is difficult to articulate the amount of gratitude I have for the support and encouragement I have received throughout my master’s thesis. Many people have added value and support to my life during this time. I am thankful for the education, experience, and friendships I have gained at the University of Central Oklahoma. First, I would like to thank Dr. Nikki Seagraves for her mentorship and friendship. I lucked out when I met her. I have enjoyed working on this project and I am very thankful for her support. I would like thank Thomas Crane for his support and patience throughout my master’s degree. I would like to thank Dr. Shannon Conley for her continued mentorship and support. I would like to thank Liz Bullen and Dr. Eric Howard for their training and help on this project. I would like to thank Kristy Meyer for her friendship and help throughout graduate school. I would like to thank my committee members Dr. Robert Brennan and Dr. Lilian Chooback for their advisement on this project. Also, I would like to thank the biology faculty and staff. I would like to thank the Seagraves lab members: Jailene Canales, Kayley Pate, Mckayla Muse, Grace Thetford, Kody Harvey, Jordan Guffey, and Kayle Patatanian for their hard work and support. -
A Long Noncoding RNA Maintains Active Chromatin to Coordinate Homeotic Gene Expression
LETTER doi:10.1038/nature09819 A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression Kevin C. Wang1,2, Yul W. Yang1*, Bo Liu3*, Amartya Sanyal4, Ryan Corces-Zimmerman1, Yong Chen5, Bryan R. Lajoie4, Angeline Protacio1, Ryan A. Flynn1, Rajnish A. Gupta1, Joanna Wysocka6, Ming Lei5, Job Dekker4, Jill A. Helms3 & Howard Y. Chang1 The genome is extensively transcribed into long intergenic non- we suggest the name HOTTIP for ‘HOXA transcript at the distal tip’, coding RNAs (lincRNAs), many of which are implicated in gene exhibits bivalent H3K4me3 and H3K27me3, a histone modification silencing1,2. Potential roles of lincRNAs in gene activation are pattern associated with poised regulatory sequences16. Comparison much less understood3–5. Development and homeostasis require with RNA polymerase II occupancy and RNA expression showed that coordinate regulation of neighbouring genes through a process the bivalent H3K4me3 and H3K27me3 modifications on HOTTIP gene termed locus control6. Some locus control elements and enhancers do not require HOTTIP transcription, but transcription of HOTTIP is transcribe lincRNAs7–10, hinting at possible roles in long-range associated with increased H3K4me3 and decreased H3K27me3 (Fig. 1a, control. In vertebrates, 39 Hox genes, encoding homeodomain left). Chromatin immunoprecipitation (ChIP) analysis confirmed that transcription factors critical for positional identity, are clustered the HOTTIP gene is occupied by both polycomb repressive complex 2 in four chromosomal loci; the Hox genes are expressed in nested (PRC2) and MLL complex, consistent with the bivalent histone marks anterior-posterior and proximal-distal patterns colinear with their (Supplementary Fig. 1a). genomic position from 39 to 59of the cluster11. -
Aberrant Activity of Histone–Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis
International Journal of Molecular Sciences Review Aberrant Activity of Histone–Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis Elzbieta Poreba 1,* , Krzysztof Lesniewicz 2 and Julia Durzynska 1,* 1 Institute of Experimental Biology, Faculty of Biology, Adam Mickiewicz University, ul. Uniwersytetu Pozna´nskiego6, 61-614 Pozna´n,Poland 2 Department of Molecular and Cellular Biology, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, ul. Uniwersytetu Pozna´nskiego6, 61-614 Pozna´n,Poland; [email protected] * Correspondence: [email protected] (E.P.); [email protected] (J.D.); Tel.: +48-61-829-5857 (E.P.) Received: 19 November 2020; Accepted: 6 December 2020; Published: 8 December 2020 Abstract: KMT2 (histone-lysine N-methyltransferase subclass 2) complexes methylate lysine 4 on the histone H3 tail at gene promoters and gene enhancers and, thus, control the process of gene transcription. These complexes not only play an essential role in normal development but have also been described as involved in the aberrant growth of tissues. KMT2 mutations resulting from the rearrangements of the KMT2A (MLL1) gene at 11q23 are associated with pediatric mixed-lineage leukemias, and recent studies demonstrate that KMT2 genes are frequently mutated in many types of human cancers. Moreover, other components of the KMT2 complexes have been reported to contribute to oncogenesis. This review summarizes the recent advances in our knowledge of the role of KMT2 complexes in cell transformation. In addition, it discusses the therapeutic targeting of different components of the KMT2 complexes. Keywords: histone–lysine N-methyltransferase 2; COMPASS; COMPASS-like; H3K4 methylation; oncogenesis; cancer; epigenetics; chromatin 1. -
Supplementary Figure S4
18DCIS 18IDC Supplementary FigureS4 22DCIS 22IDC C D B A E (0.77) (0.78) 16DCIS 14DCIS 28DCIS 16IDC 28IDC (0.43) (0.49) 0 ADAMTS12 (p.E1469K) 14IDC ERBB2, LASP1,CDK12( CCNE1 ( NUTM2B SDHC,FCGR2B,PBX1,TPR( CD1D, B4GALT3, BCL9, FLG,NUP21OL,TPM3,TDRD10,RIT1,LMNA,PRCC,NTRK1 0 ADAMTS16 (p.E67K) (0.67) (0.89) (0.54) 0 ARHGEF38 (p.P179Hfs*29) 0 ATG9B (p.P823S) (0.68) (1.0) ARID5B, CCDC6 CCNE1, TSHZ3,CEP89 CREB3L2,TRIM24 BRAF, EGFR (7p11); 0 ABRACL (p.R35H) 0 CATSPER1 (p.P152H) 0 ADAMTS18 (p.Y799C) 19q12 0 CCDC88C (p.X1371_splice) (0) 0 ADRA1A (p.P327L) (10q22.3) 0 CCNF (p.D637N) −4 −2 −4 −2 0 AKAP4 (p.G454A) 0 CDYL (p.Y353Lfs*5) −4 −2 Log2 Ratio Log2 Ratio −4 −2 Log2 Ratio Log2 Ratio 0 2 4 0 2 4 0 ARID2 (p.R1068H) 0 COL27A1 (p.G646E) 0 2 4 0 2 4 2 EDRF1 (p.E521K) 0 ARPP21 (p.P791L) ) 0 DDX11 (p.E78K) 2 GPR101, p.A174V 0 ARPP21 (p.P791T) 0 DMGDH (p.W606C) 5 ANP32B, p.G237S 16IDC (Ploidy:2.01) 16DCIS (Ploidy:2.02) 14IDC (Ploidy:2.01) 14DCIS (Ploidy:2.9) -3 -2 -1 -3 -2 -1 -3 -2 -1 -3 -2 -1 -3 -2 -1 -3 -2 -1 Log Ratio Log Ratio Log Ratio Log Ratio 12DCIS 0 ASPM (p.S222T) Log Ratio Log Ratio 0 FMN2 (p.G941A) 20 1 2 3 2 0 1 2 3 2 ERBB3 (p.D297Y) 2 0 1 2 3 20 1 2 3 0 ATRX (p.L1276I) 20 1 2 3 2 0 1 2 3 0 GALNT18 (p.F92L) 2 MAPK4, p.H147Y 0 GALNTL6 (p.E236K) 5 C11orf1, p.Y53C (10q21.2); 0 ATRX (p.R1401W) PIK3CA, p.H1047R 28IDC (Ploidy:2.0) 28DCIS (Ploidy:2.0) 22IDC (Ploidy:3.7) 22DCIS (Ploidy:4.1) 18IDC (Ploidy:3.9) 18DCIS (Ploidy:2.3) 17q12 0 HCFC1 (p.S2025C) 2 LCMT1 (p.S34A) 0 ATXN7L2 (p.X453_splice) SPEN, p.P677Lfs*13 CBFB 1 2 3 4 5 6 7 8 9 10 11 -
The Regulation of Lunatic Fringe During Somitogenesis
THE REGULATION OF LUNATIC FRINGE DURING SOMITOGENESIS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Emily T. Shifley ***** The Ohio State University 2009 Dissertation Committee: Approved by Professor Susan Cole, Advisor Professor Christine Beattie _________________________________ Professor Mark Seeger Advisor Graduate Program in Molecular Genetics Professor Michael Weinstein ABSTRACT Somitogenesis is the morphological hallmark of vertebrate segmentation. Somites bud from the presomitic mesoderm (PSM) in a sequential, periodic fashion and give rise to the rib cage, vertebrae, and dermis and muscles of the back. The regulation of somitogenesis is complex. In the posterior region of the PSM, a segmentation clock operates to organize cohorts of cells into presomites, while in the anterior region of the PSM the presomites are patterned into rostral and caudal compartments (R/C patterning). Both of these stages of somitogenesis are controlled, at least in part, by the Notch pathway and Lunatic fringe (Lfng), a glycosyltransferase that modifies the Notch receptor. To dissect the roles played by Lfng during somitogenesis, we created a novel allele that lacks cyclic Lfng expression within the segmentation clock, but that maintains expression during R/C somite patterning (Lfng∆FCE1). Lfng∆FCE1/∆FCE1 mice have severe defects in their anterior vertebrae and rib cages, but relatively normal sacral and tail vertebrae, unlike Lfng knockouts. Segmentation clock function is differentially affected by the ∆FCE1 deletion; during anterior somitogenesis the expression patterns of many clock genes are disrupted, while during posterior somitogenesis, certain clock components have recovered. R/C patterning occurs relatively normally in Lfng∆FCE1/∆FCE1 embryos, likely contributing to the partial phenotype rescue, and confirming that Lfng ii plays separate roles in the two regions of the PSM. -
Replication and Kinetic Trapping of Nucleic Acids in Alternative Environments
REPLICATION AND KINETIC TRAPPING OF NUCLEIC ACIDS IN ALTERNATIVE ENVIRONMENTS A Dissertation Presented to The Academic Faculty by Adriana Lozoya Colinas In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the School of Chemistry and Biochemistry Georgia Institute of Technology December 2020 COPYRIGHT © 2020 BY ADRIANA LOZOYA COLINAS REPLICATION AND KINETIC TRAPPING OF NUCLEIC ACIDS IN ALTERNATIVE ENVIRONMENTS Approved by: Dr. Nicholas V. Hud, Advisor Dr. Amanda Stockton School of Chemistry and Biochemistry School of Chemistry and Biochemistry Georgia Institute of Technology Georgia Institute of Technology Dr. Martha A. Grover Dr. Adegboyega (Yomi) Oyelere School of Chemical & Biomolecular School of Chemistry and Biochemistry Engineering Georgia Institute of Technology Georgia Institute of Technology Dr. Loren Williams School of Chemistry and Biochemistry Georgia Institute of Technology Date Approved: October 16, 2020 ACKNOWLEDGEMENTS I would like to thank my mom and dad for all their support and setting up an example for me to follow. I really appreciate everything you have done to encourage me to succeed and follow my dreams. I want to thank Mario for always supporting me. I know it hasn’t always been easy being far away, thank you for being patient and supportive with me. Thank you for the time and adventures we lived together. To all my Latino family at Georgia Tech, thank you for making me feel closer to home. We spent a lot of time together, learned a lot from each other and shared our culture, all of which have made my PhD experience more enjoyable. I would also like to acknowledge my advisor, Nick Hud, for being supportive and sharing his passion for science with me. -
Guide for Morpholino Users: Toward Therapeutics
Open Access Journal of Drug Discovery, Development and Delivery Special Article - Antisense Drug Research and Development Guide for Morpholino Users: Toward Therapeutics Moulton JD* Gene Tools, LLC, USA Abstract *Corresponding author: Moulton JD, Gene Tools, Morpholino oligos are uncharged molecules for blocking sites on RNA. They LLC, 1001 Summerton Way, Philomath, Oregon 97370, are specific, soluble, non-toxic, stable, and effective antisense reagents suitable USA for development as therapeutics and currently in clinical trials. They are very versatile, targeting a wide range of RNA targets for outcomes such as blocking Received: January 28, 2016; Accepted: April 29, 2016; translation, modifying splicing of pre-mRNA, inhibiting miRNA maturation and Published: May 03, 2016 activity, as well as less common biological targets and diagnostic applications. Solutions have been developed for delivery into a range of cultured cells, embryos and adult animals; with development of a non-toxic and effective system for systemic delivery, Morpholinos have potential for broad therapeutic development targeting pathogens and genetic disorders. Keywords: Splicing; Duchenne muscular dystrophy; Phosphorodiamidate morpholino oligos; Internal ribosome entry site; Nonsense-mediated decay Morpholinos: Research Applications, the transcript from miRNA regulation; Therapeutic Promise • Block regulatory proteins from binding to RNA, shifting Morpholino oligos bind to complementary sequences of RNA alternative splicing; and get in the way of processes. Morpholino oligos are commonly • Block association of RNAs with cytoskeletal motor protein used to prevent a particular protein from being made in an organism complexes, preventing RNA translocation; or cell culture. Morpholinos are not the only tool used for this: a protein’s synthesis can be inhibited by altering DNA to make a null • Inhibit poly-A tailing of pre-mRNA; mutant (called a gene knockout) or by interrupting processes on RNA • Trigger frame shifts at slippery sequences; (called a gene knockdown). -
Modeling the Human Segmentation Clock with Pluripotent Stem Cells 2 3 Mitsuhiro Matsuda1,10, Yoshihiro Yamanaka2,10, Maya Uemura2,3, Mitsujiro Osawa4, 4 Megumu K
bioRxiv preprint doi: https://doi.org/10.1101/562447; this version posted February 27, 2019. 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. 1 Modeling the Human Segmentation Clock with Pluripotent Stem Cells 2 3 Mitsuhiro Matsuda1,10, Yoshihiro Yamanaka2,10, Maya Uemura2,3, Mitsujiro Osawa4, 4 Megumu K. Saito4, Ayako Nagahashi4, Megumi Nishio3, Long Guo5, Shiro Ikegawa5, 5 Satoko Sakurai6, Shunsuke Kihara7, Michiko Nakamura6, Tomoko Matsumoto6, Hiroyuki 6 Yoshitomi2,3, Makoto Ikeya6, Takuya Yamamoto6,8, Knut Woltjen6,9, Miki Ebisuya1*, 7 Junya Toguchida2,3, Cantas Alev2* 8 9 1 Laboratory for Reconstitutive Developmental Biology, RIKEN Center for Biosystems 10 Dynamics Research (RIKEN BDR), Kobe 650-0047, Japan. 11 2 Department of Cell Growth and Differentiation, Center for iPS Cell Research and 12 Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. 13 3 Department of Regeneration Science and Engineering, Institute for Frontier Life and 14 Medical Sciences, Kyoto University, Kyoto 606-8507, Japan. 15 4 Department of Clinical Application, Center for iPS Cell Research and Application 16 (CiRA), Kyoto University, Kyoto 606-8507, Japan. 17 5 Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical 18 Sciences (RIKEN IMS), Tokyo 108-8639, Japan. 19 6 Department of Life Science Frontiers, Center for iPS Cell Research and Application 20 (CiRA), Kyoto University, 606-8507, Kyoto 108-8639, Japan. 21 7 Department of Fundamental Cell Technology, Center for iPS Cell Research and 22 Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. 23 8 AMED-CREST, AMED 1-7-1 Otemachi, Chiyodaku, Tokyo 100-004, Japan.