Neurobiological Functions of the Period Circadian Clock 2 Gene, Per2
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Distinct Patterns of Period Gene Expression in the Suprachiasmatic Nucleus Underlie Circadian Clock Photoentrainment by Advances Or Delays
University of Massachusetts Medical School eScholarship@UMMS Neurobiology Publications and Presentations Neurobiology 2011-10-11 Distinct patterns of Period gene expression in the suprachiasmatic nucleus underlie circadian clock photoentrainment by advances or delays William J. Schwartz University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/neurobiology_pp Part of the Neuroscience and Neurobiology Commons Repository Citation Schwartz WJ, Tavakoli-Nezhad M, Lambert CM, Weaver DR, de la Iglesia HO. (2011). Distinct patterns of Period gene expression in the suprachiasmatic nucleus underlie circadian clock photoentrainment by advances or delays. Neurobiology Publications and Presentations. https://doi.org/10.1073/ pnas.1107848108. Retrieved from https://escholarship.umassmed.edu/neurobiology_pp/114 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Neurobiology Publications and Presentations by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Distinct patterns of Period gene expression in the suprachiasmatic nucleus underlie circadian clock photoentrainment by advances or delays William J. Schwartza,1, Mahboubeh Tavakoli-Nezhada, Christopher M. Lambertb, David R. Weaverb, and Horacio O. de la Iglesiac,1 Departments of aNeurology and bNeurobiology, University of Massachusetts Medical School, Worcester, MA 01655; and cDepartment of Biology, University of Washington, Seattle, WA 98195 Edited by Michael Rosbash, Howard Hughes Medical Institute, Waltham, MA, and approved September 9, 2011 (received for review May 19, 2011) The circadian clock in the mammalian hypothalamic suprachias- and Per3) genes is activated. PER proteins accumulate in the matic nucleus (SCN) is entrained by the ambient light/dark cycle, cytoplasm, are regulated through their phosphorylation and their which differentially acts to cause the clock to advance or delay. -
RNA-Binding Protein Hnrnpll Regulates Mrna Splicing and Stability During B-Cell to Plasma-Cell Differentiation
RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation Xing Changa,b, Bin Lic, and Anjana Raoa,b,d,e,1 Divisions of aSignaling and Gene Expression and cVaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; bSanford Consortium for Regenerative Medicine, La Jolla, CA 92037; and dDepartment of Pharmacology and eMoores Cancer Center, University of California at San Diego, La Jolla, CA 92093 Contributed by Anjana Rao, December 2, 2014 (sent for review July 20, 2014) Posttranscriptional regulation is a major mechanism to rewire the RBP-binding sites, thus validating the specificity of RBP binding transcriptomes during differentiation. Heterogeneous nuclear to coprecipitating RNAs and mapping RBP-binding sites on the RNA-binding protein LL (hnRNPLL) is specifically induced in terminally validated RNAs at close to single-nucleotide resolution (8). differentiated lymphocytes, including effector T cells and plasma Heterogeneous nuclear RNA-binding proteins (hnRNPs) is cells. To study the molecular functions of hnRNPLL at a genome- the term applied to a collection of unrelated nuclear RBPs. wide level, we identified hnRNPLL RNA targets and binding sites in hnRNPLL was identified through a targeted lentiviral shRNA plasma cells through integrated Photoactivatable-Ribonucleoside- screen for regulators of CD45RA to CD45RO switching during Enhanced Cross-Linking and Immunoprecipitation (PAR-CLIP) and memory T-cell development (9) and independently through RNA sequencing. hnRNPLL preferentially recognizes CA dinucleo- two separate screens performed by different groups for exclusion tide-containing sequences in introns and 3′ untranslated regions of CD45 exon 4 in a minigene context (10) and for altered CD44 (UTRs), promotes exon inclusion or exclusion in a context-dependent and CD45R expression on T cells in N-ethyl-N-nitrosourea manner, and stabilizes mRNA when associated with 3′ UTRs. -
TGF-Β1 Signaling Targets Metastasis-Associated Protein 1, a New Effector in Epithelial Cells
Oncogene (2011) 30, 2230–2241 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc ORIGINAL ARTICLE TGF-b1 signaling targets metastasis-associated protein 1, a new effector in epithelial cells SB Pakala1, K Singh1,3, SDN Reddy1, K Ohshiro1, D-Q Li1, L Mishra2 and R Kumar1 1Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, The George Washington University Medical Center, Washington, DC, USA and 2Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA In spite of a large number of transforming growth factor b1 gene chromatin in response to upstream signals. The (TGF-b1)-regulated genes, the nature of its targets with TGF-b1-signaling is largely mediated by Smad proteins roles in transformation continues to be poorly understood. (Massague et al., 2005) where Smad2 and Smad3 are Here, we discovered that TGF-b1 stimulates transcription phosphorylated by TGF-b1-receptors and associate with of metastasis-associated protein 1 (MTA1), a dual master the common mediator Smad4, which translocates to the coregulator, in epithelial cells, and that MTA1 status is a nucleus to participate in the expression of TGF-b1-target determinant of TGF-b1-induced epithelial-to-mesenchymal genes (Deckers et al., 2006). Previous studies have shown transition (EMT) phenotypes. In addition, we found that that CUTL1, also known as CDP (CCAAT displacement MTA1/polymerase II/activator protein-1 (AP-1) co-activator protein), a target of TGF-b1, is needed for its short-term complex interacts with the FosB-gene chromatin and stimu- effects of TGF-b1 on cell motility involving Smad4- lates its transcription, and FosB in turn, utilizes FosB/histone dependent pathway (Michl et al.,2005). -
Regulation of Drosophila Circadian Rhythms by Mirna Let-7 Is Mediated by a Regulatory Cycle
ARTICLE Received 10 Jul 2014 | Accepted 10 Oct 2014 | Published 24 Nov 2014 DOI: 10.1038/ncomms6549 Regulation of Drosophila circadian rhythms by miRNA let-7 is mediated by a regulatory cycle Wenfeng Chen1,*, Zhenxing Liu1,*, Tianjiao Li1, Ruifeng Zhang1, Yongbo Xue1, Yang Zhong1, Weiwei Bai1, Dasen Zhou1 & Zhangwu Zhao1 MicroRNA-mediated post-transcriptional regulations are increasingly recognized as important components of the circadian rhythm. Here we identify microRNA let-7, part of the Drosophila let-7-Complex, as a regulator of circadian rhythms mediated by a circadian regulatory cycle. Overexpression of let-7 in clock neurons lengthens circadian period and its deletion attenuates the morning activity peak as well as molecular oscillation. Let-7 regulates the circadian rhythm via repression of CLOCKWORK ORANGE (CWO). Conversely, upregulated cwo in cwo-expressing cells can rescue the phenotype of let-7-Complex overexpression. Moreover, circadian prothoracicotropic hormone (PTTH) and CLOCK- regulated 20-OH ecdysteroid signalling contribute to the circadian expression of let-7 through the 20-OH ecdysteroid receptor. Thus, we find a regulatory cycle involving PTTH, a direct target of CLOCK, and PTTH-driven miRNA let-7. 1 Department of Entomology, College of Agronomy and Biotechnology, China Agricultural University, Beijing 100193, China. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to Z.Z. (email: [email protected]). NATURE COMMUNICATIONS | 5:5549 | DOI: 10.1038/ncomms6549 | www.nature.com/naturecommunications 1 & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms6549 lmost all animals display a wide range of circadian bantam-dependent regulation of Clk expression is required for rhythms in behaviour and physiology, such as locomotor circadian rhythm. -
A Circadian Biomarker Associated with Breast Cancer in Young Women
268 Cancer Epidemiology, Biomarkers & Prevention Period3 Structural Variation: A Circadian Biomarker Associated with Breast Cancer in Young Women Yong Zhu,1 Heather N. Brown,1 Yawei Zhang,1 Richard G. Stevens,2 and Tongzhang Zheng1 1Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut and 2University of Connecticut Health Center, Farmington, Connecticut Abstract Circadian disruption has been indicated as a risk factor for blood samples collected from a recently completed breast breast cancer in recent epidemiologic studies. A novel cancer case-control study in Connecticut. There were 389 finding in circadian biology is that genes responsible for Caucasian cases and 432 Caucasian controls included in our circadian rhythm also regulate many other biological path- analysis. We found that the variant Per3 genotype (heterozy- ways, including cell proliferation, cell cycle regulation, and gous + homozygous 5-repeat alleles) was associated with an apoptosis. Therefore, mutations in circadian genes could increased risk of breast cancer among premenopausal women conceivably result in deregulation of these processes and (odds ratio, 1.7; 95% confidence interval, 1.0-3.0). Our find- contribute to tumor development, and be markers for ing suggests that the circadian genes might be a novel panel susceptibility to human cancer. In this study, we investi- of potential biomarkers for breast cancer and worth further gated the association between an exonic length variation in a investigation. (Cancer Epidemiol Biomarkers Prev circadian gene, Period3 (Per3), and breast cancer risk using 2005;14(1):268–70) Introduction Genetic determinants have been found to be responsible for a Per2 gene can activate c-Myc signaling pathways leading to fundamental biological phenomenon: a universal 24-hour genomic instability and cell proliferation. -
UNIVERSITY of CALIFORNIA Los Angeles
UNIVERSITY OF CALIFORNIA Los Angeles Circadian Gene Networks In Bone Regeneration A thesis submitted in partial satisfaction of the requirements for the degree Master of Science in Oral Biology by Nathaniel Raphael Hassan 2012 ABSTRACT OF THESIS Circadian Gene Networks In Bone Regeneration By Nathaniel Raphael Hassan Master of Science in Oral Biology University of California, Los Angeles, 2012 Professor Ichiro Nishimura, Chair BACKGROUND: Previous studies suggested that vitamin D played a significant role in bone regeneration, facilitating the establishment of implant osseointegration. A whole genome microarray study further suggested that the vitamin D axis might involve circadian rhythm gene expression in the bone peripheral tissue. OBJECTIVES: To identify key gene networks involved with vitamin D receptor in the bone regeneration process and to explore any correlation with circadian rhythm gene expression in bone marrow mesenchymal stromal/stem cells (BMSC). METHODS: The available whole gene microarray data was analyzed using the weighted gene correlation network analysis (WGCNA) R package and Cytoscape software. Any gene expression correlation was examined for vitamin D receptor (VDR) as well as circadian rhythm ii genes. Separately, Per 1 luciferase transgenic Wistar rats were then applied for in vitro evaluation on BMSC circadian rhythm. Per1::luc BMSCs were seeded on 35mm dishes and forskolin-synchronized luminescence was recorded across different media conditions. The recording media included growth medium containing F12 (10% Fetal Bovine Serum, 1% Pen- Strep and antibiotic) supplemented with or without 1 nM 1,25D. Luminescence was also recorded in F12 growth medium containing bone differentiation factors (beta glycerophosphate, Ascorbic acid and Dexamethasone) supplemented with 0, 1 or 10 nM 1,25D. -
NPAS2 As a Transcriptional Regulator of Non-Rapid Eye Movement Sleep: Genotype and Sex Interactions
NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: Genotype and sex interactions Paul Franken*†‡, Carol A. Dudley§, Sandi Jo Estill§, Monique Barakat*, Ryan Thomason¶, Bruce F. O’Hara¶, and Steven L. McKnight‡§ §Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390; *Department of Biological Sciences, Stanford University, Stanford, CA 94305; ¶Department of Biology, University of Kentucky, Lexington, KY 40506; and †Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne-Dorigny, Switzerland Contributed by Steven L. McKnight, March 13, 2006 Because the transcription factor neuronal Per-Arnt-Sim-type sig- delta frequency range is a sensitive marker of time spent awake (4, nal-sensor protein-domain protein 2 (NPAS2) acts both as a sensor 7) and local cortical activation (8) and is therefore widely used as and an effector of intracellular energy balance, and because sleep an index of NREMS need and intensity. is thought to correct an energy imbalance incurred during waking, The PAS-domain proteins, CLOCK, BMAL1, PERIOD-1 we examined NPAS2’s role in sleep homeostasis using npas2 (PER1), and PER2, play crucial roles in circadian rhythm gener- knockout (npas2؊/؊) mice. We found that, under conditions of ation (9). The NPAS2 paralog CLOCK, like NPAS2, can induce the increased sleep need, i.e., at the end of the active period or after transcription of per1, per2, cryptochrome-1 (cry1), and cry2. PER and sleep deprivation (SD), NPAS2 allows for sleep to occur at times CRY proteins, in turn, inhibit CLOCK- and NPAS2-induced when mice are normally awake. Lack of npas2 affected electroen- transcription, thereby closing a negative-feedback loop that is cephalogram activity of thalamocortical origin; during non-rapid thought to underlie circadian rhythm generation. -
Spatial and Temporal Expression of the Period and Timeless Genes in the Developing Nervous System of Drosophila
The Journal of Neuroscience, September 1, 1997, 17(17):6745–6760 Spatial and Temporal Expression of the period and timeless Genes in the Developing Nervous System of Drosophila: Newly Identified Pacemaker Candidates and Novel Features of Clock Gene Product Cycling Maki Kaneko,1 Charlotte Helfrich-Fo¨ rster,2 and Jeffrey C. Hall1 1Department of Biology, Brandeis University, Waltham, Massachusetts 02254, and 2Botanisches Institut, 72076 Tu¨ bingen, Germany The circadian timekeeping system of Drosophila functions from onward, throughout metamorphosis and into adulthood. There- the first larval instar (L1) onward but is not known to require the fore, they are the best candidates for being pacemaker neurons expression of clock genes in larvae. We show that period ( per) responsible for the larval “time memory” (inferred from previous and timeless (tim) are rhythmically expressed in several groups experiments). In addition to the LNs, a subset of the larval of neurons in the larval CNS both in light/dark cycles and in dorsal neurons (DNLs) expresses per and tim. Intriguingly, two constant dark conditions. Among the clock gene-expressing neurons of this DNL group cycle in PER and TIM immunoreac- cells there is a subset of the putative pacemaker neurons, the tivity almost in antiphase to the other DNLs and to the LNs. “lateral neurons” (LNs), that have been analyzed mainly in adult Thus, the temporal expression of per and tim are regulated flies. Like the adult LNs, the larval ones are also immunoreac- differentially in different cells. Furthermore, the light sensitivity tive to a peptide called pigment-dispersing hormone. Their associated with levels of the TIM protein is different from that in putative dendritic trees were found to be in close proximity to the heads of adult Drosophila. -
Overexpression of C-Myc in -Cells of Transgenic Mice Causes Proliferation and Apoptosis, Downregulation of Insulin Gene Expression, and Diabetes D
Overexpression of c-Myc in -Cells of Transgenic Mice Causes Proliferation and Apoptosis, Downregulation of Insulin Gene Expression, and Diabetes D. Ross Laybutt,1 Gordon C. Weir,1 Hideaki Kaneto,1 Judith Lebet,1 Richard D. Palmiter,2 Arun Sharma,1 and Susan Bonner-Weir1 To test the hypothesis that c-Myc plays an important role in -cell growth and differentiation, we generated transgenic mice overexpressing c-Myc in -cells under ancreatic -cell failure is fundamental to the control of the rat insulin II promoter. F1 transgenic pathogenesis of all forms of diabetes (1,2). Stud- mice from two founders developed neonatal diabetes ies from animal models suggest that, for the most (associated with reduced plasma insulin levels) and part, -cells have a remarkable capacity to in- died of hyperglycemia 3 days after birth. In pancreata of P crease their mass and secretion to maintain plasma glu- transgenic mice, marked hyperplasia of cells with an altered phenotype and amorphous islet organization cose levels within a narrow range, even in the presence of was displayed: islet volume was increased threefold obesity and insulin resistance (1–4). Diabetes develops versus wild-type littermates. Apoptotic nuclei were in- only when this compensation is inadequate. creased fourfold in transgenic versus wild-type mice, In animal models of diabetes, -cells have been found to suggesting an increased turnover of -cells. Very few lose the unique differentiation that optimizes glucose- cells immunostained for insulin; pancreatic insulin induced insulin secretion and synthesis (5,6). Thus, mRNA and content were markedly reduced. GLUT2 genes that are highly expressed (insulin, GLUT2, and  mRNA was decreased, but other -cell–associated genes PDX-1 [pancreatic and duodenal homeobox-1]) are de- (IAPP [islet amyloid pancreatic polypeptide], PDX-1 [pancreatic and duodenal homeobox-1], and BETA2/ creased with diabetes, whereas several genes that are NeuroD) were expressed at near-normal levels. -
Play Clock Operator Guide
NFHS GENERAL INSTRUCTIONS FOR FOOTBALL GAME AND PLAY CLOCK OPERATORS A. The game and play clock operators should report to the game officials at the stadium at least 30 minutes before game time for the following purposes: 1. To synchronize timer’s watch with official game time as established by the game official responsible for timing. 2. To advise game officials whether the game clock operator and/or play clock operator will be in the press box or on the field/side- line. Determine procedure for communications with both operators and test procedures prior to the games. 3. To discuss coordination of starting, stopping and adjusting the game clock or play clock in accordance with the playing rules. 4. To discuss if the game clock horn (mechanical signal) can be turned off. Preference is for the game clock horn (mechanical signal) to be turned off for the duration of the game. B. The game clock is normally started 30 minutes before game time. The halftime intermission will start on the referee’s signal when the players and game officials leave the field. All pregame and halftime activities shall be synchronized with the game clock. The mandatory three-minute warm-up period will be put on the game clock after the intermission time has elapsed and shall be started immediately. C. The game clock operator shall have an extra stopwatch available. In case of failure of the game clock, the game clock operator shall immediately contact the game officials, giving them the correct data regarding the official time. The game official responsible for timing will then pick up the correct game time on the stopwatch. -
Agonists and Knockdown of Estrogen Receptor Β Differentially Affect
Schüler-Toprak et al. BMC Cancer (2016) 16:951 DOI 10.1186/s12885-016-2973-y RESEARCH ARTICLE Open Access Agonists and knockdown of estrogen receptor β differentially affect invasion of triple-negative breast cancer cells in vitro Susanne Schüler-Toprak1*, Julia Häring1, Elisabeth C. Inwald1, Christoph Moehle2, Olaf Ortmann1 and Oliver Treeck1 Abstract Background: Estrogen receptor β (ERβ) is expressed in the majority of invasive breast cancer cases, irrespective of their subtype, including triple-negative breast cancer (TNBC). Thus, ERβ might be a potential target for therapy of this challenging cancer type. In this in vitro study, we examined the role of ERβ in invasion of two triple-negative breast cancer cell lines. Methods: MDA-MB-231 and HS578T breast cancer cells were treated with the specific ERβ agonists ERB-041, WAY200070, Liquiritigenin and 3β-Adiol. Knockdown of ERβ expression was performed by means of siRNA transfection. Effects on cellular invasion were assessed in vitro by means of a modified Boyden chamber assay. Transcriptome analyses were performed using Affymetrix Human Gene 1.0 ST microarrays. Pathway and gene network analyses were performed by means of Genomatix and Ingenuity Pathway Analysis software. Results: Invasiveness of MBA-MB-231 and HS578T breast cancer cells decreased after treatment with ERβ agonists ERB-041 and WAY200070. Agonists Liquiritigenin and 3β-Adiol only reduced invasion of MDA-MB-231 cells. Knockdown of ERβ expression increased invasiveness of MDA-MB-231 cells about 3-fold. Transcriptome and pathway analyses revealed that ERβ knockdown led to activation of TGFβ signalling and induced expression of a network of genes with functions in extracellular matrix, tumor cell invasion and vitamin D3 metabolism. -
Cross-Family Dimerization of Transcription Factors Fos/Jun
Proc. Nati. Acad. Sci. USA Vol. 88, pp. 3720-3724, May 9, 1991 Biochemistry Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity (gene regulation/oncogenes/leucine zipper/protein dimerization/transcription) TSONWIN HAI*t AND ToM CURRANt of Medical Biochemistry and Ohio State Biotechnology Center, Ohio State University, 1060 Carmack Road, Columbus, OH 43210; and tDepartment*Department of Molecular Oncology and Virology, Roche Institute of Molecular Biology, Roche Research Center, Nutley, NJ 07110 Communicated by Herbert Weissbach, January 31, 1991 ABSTRACT The Fos/Jun and ATF/CREB families of Table 1. Mammalian Fos/Jun and ATF/CREB families transcription factors function in coupling extracellular signals Family Subfamily Gene(s) to alterations in expression of specific target genes. Like many eukaryotic transcription factors, these proteins bind to DNA as Fos/Jun Fos fos, fra-), fra-2, fosB dimers. Dimerization is mediated by a structure known as the Jun c-jun, junB, junD "leucine-zipper" motif. Although Fos/Jun and ATF/CREB ATF/CREB CREB CREB, ATF-I were previously thought to interact preferentially with differ- CRE-BP1 CRE-BPI, ATF-a ent DNA regulatory elements (the AP-1/TRE and ATF/CRE ATF-3 ATF-3* sites, respectively), we rind that members of these two families ATF-4 ATF4* form selective cross-family heterodimers. The resulting het- Alternative names for CRE-BPI are ATF-2 and HB16. ACREB is erodimers display distinguishable DNA binding speclfcities a spliced variant ofCREB, ATF-aA is a spliced variant ofATF-a, and from each other and from their parental homodimers.