Linking Autism Risk Genes to Disruption of Cortical Development
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Microrna Function: Multiple Mechanisms for a Tiny RNA?
Downloaded from rnajournal.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW MicroRNA function: Multiple mechanisms for a tiny RNA? RAMESH S. PILLAI Friedrich Miescher Institute for Biomedical Research, 4002 Basel, Switzerland ABSTRACT MicroRNAs are sequence-specific regulators of post-transcriptional gene expression in many eukaryotes. They are believed to control the expression of thousands of target mRNAs, with each mRNA believed to be targeted by multiple microRNAs. Recent studies have uncovered various mechanisms by which microRNAs down-regulate their target mRNAs and have linked a well- known subcellular structure, the cytoplasmic processing bodies (PBs) to the microRNA pathway. The finding that microRNAs are misexpressed in cancers has reinforced the idea that their regulatory roles are very important. Keywords: microRNAs; miRNPs; translational repression; P-bodies; Argonaute INTRODUCTION that the forced overexpression of miRNAs can lead to the development of tumors (He et al. 2005). MicroRNAs (miRNAs) have come a long way from being Another pathway that uses small RNAs as sequence-spe- an oddity of worms when they were first discovered over 10 cific regulators is the RNA interference (RNAi) pathway, years ago (Lee et al. 1993) to be recognized now as novel which is an evolutionarily conserved response to the pres- agents exercising post-transcriptional control over most ence of double-stranded RNA (dsRNA) in the cell (Meister eukaryotic genomes. They are a family of 21–25-nucleotides and Tuschl 2004; Filipowicz 2005). The dsRNAs are cleaved (nt)-long RNAs expressed in a wide variety of organisms into 20-base pair (bp) duplexes of small-interfering RNAs ranging from plants to worms and humans. -
422.Full.Pdf
Downloaded from genome.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Research Dioxin receptor and SLUG transcription factors regulate the insulator activity of B1 SINE retrotransposons via an RNA polymerase switch Angel Carlos Roma´n,1 Francisco J. Gonza´lez-Rico,1 Eduardo Molto´,2,3 Henar Hernando,4 Ana Neto,5 Cristina Vicente-Garcia,2,3 Esteban Ballestar,4 Jose´ L. Go´mez-Skarmeta,5 Jana Vavrova-Anderson,6 Robert J. White,6,7 Lluı´s Montoliu,2,3 and Pedro M. Ferna´ndez-Salguero1,8 1Departamento de Bioquı´mica y Biologı´a Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain; 2Centro Nacional de Biotecnologı´a (CNB), Consejo Superior de Investigaciones Cientı´ficas (CSIC), Department of Molecular and Cellular Biology, Campus de Cantoblanco, C/Darwin 3, 28049 Madrid, Spain; 3Centro de Investigacio´n Biome´dica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; 4Chromatin and Disease Group, Cancer Epigenetics and Biology Programme, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona 08907, Spain; 5Centro Andaluz de Biologı´a del Desarrollo, CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; 6College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom; 7Beatson Institute for Cancer Research, Glasgow, G61 1BD, United Kingdom Complex genomes utilize insulators and boundary elements to help define spatial and temporal gene expression patterns. We report that a genome-wide B1 SINE (Short Interspersed Nuclear Element) retrotransposon (B1-X35S) has potent in- trinsic insulator activity in cultured cells and live animals. This insulation is mediated by binding of the transcription factors dioxin receptor (AHR) and SLUG (SNAI2) to consensus elements present in the SINE. -
Activating Transcription Factor 6 Derepression Mediates Neuroprotection in Huntington Disease
Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease José R. Naranjo, … , Jia-Yi Li, Britt Mellström J Clin Invest. 2016;126(2):627-638. https://doi.org/10.1172/JCI82670. Research Article Neuroscience Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD. Find the latest version: https://jci.me/82670/pdf The Journal of Clinical Investigation RESEARCH ARTICLE Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease José R. Naranjo,1,2 Hongyu Zhang,3 Diego Villar,1,2 Paz González,1,2 Xose M. Dopazo,1,2 Javier Morón-Oset,1,2 Elena Higueras,1,2 Juan C. -
Autism Ontario Genetics Webinar EN.Pdf
Autism Ontario Genetics Webinar Thursday October 29, 2020 12:00 – 1:00 pm Panelist Stephen Scherer, PhD - Scientist Ny Hoang, MS, CGC – Genetic Counsellor Ryan Yuen, PhD - Scientist Evdokia Anagnostou, MD - Child Neurologist Autism Spectrum Disorders weak genetic factor Complex Multifactorial Condition strong genetic factor environmental factors Genetic contribution is highly variable Strong genetic Moderate genetic Weaker genetic factor factor factor Examples of genetic factors: SHANK3, NRXN1, CHD8, ARID1B, 16p13.11, 22q11 Genetic contribution is a biological difference chromosome Cell DNA sequence Protein Genetic contribution is a biological difference chromosome Cell DNA sequence genetic variant Protein not working Protein Protein not working DNA sequence genetic variant Deletions & Duplications Single Nucleotide Variations 1q21.1 deletions/ duplications CHD8, ARID1B, SCN2A, SYNGAP1, 16p13.11 deletions/ duplications SHANK3, ANK2, GRIN2B, CHD2 NRXN3, ASTN2, MBD5, PTCHD1 DNA sequence genetic variant Repeat Expansions Example: Fragile X syndrome (FMR1) CGGCGGCGGCGGCGG Normal repeat size: 5-40 CGGCGGCGGCGGCGGCGGCGGCGGCGG Syndrome repeat size: >200 DNA sequence genetic variant Repeat Expansions Fragile X syndrome (FMR1), repeat >200 • Disorders linked to well- CGG defined repeat pattern (motif) Friedreich Ataxia (FXN), repeat >100 • Only one pattern per disorder GAA • Myotonic dystrophy Type 1 (DMPK), repeat >50 Normal repeat size range CTG known Huntington’s Disease (HTT), repeat >35 CAG Spinocerebellar Ataxia Type 10 (ATXN10), repeat >800 -
Discovery of Progenitor Cell Signatures by Time-Series Synexpression Analysis During Drosophila Embryonic Cell Immortalization
Correction DEVELOPMENTAL BIOLOGY Correction for “Discovery of progenitor cell signatures by time- series synexpression analysis during Drosophila embryonic cell immortalization,” by Mary-Lee Dequéant, Delphine Fagegaltier, Yanhui Hu, Kerstin Spirohn, Amanda Simcox, Gregory J. Hannon, and Norbert Perrimon, which appeared in issue 42, October 20, 2015, of Proc Natl Acad Sci USA (112:12974–12979; first published October 5, 2015; 10.1073/pnas.1517729112). The authors note that Delphine Fagegaltier should be credited for designing research and performing research. The authors also note that Delphine Fagegaltier, Amanda Simcox, and Gregory J. Hannon should be credited for contributing to the writing of the paper. The corrected author contributions footnote appears below. Author contributions: M.-L.D., D.F., A.S., G.J.H., and N.P. designed research; M.-L.D., D.F., K.S., and A.S. performed research; M.-L.D., D.F., and Y.H. analyzed data; and M.-L.D. and N.P. wrote the paper with contributions from D.F., A.S., and G.J.H. www.pnas.org/cgi/doi/10.1073/pnas.1520482112 E6408 | PNAS | November 17, 2015 | vol. 112 | no. 46 www.pnas.org Downloaded by guest on September 25, 2021 Discovery of progenitor cell signatures by time-series synexpression analysis during Drosophila embryonic cell immortalization Mary-Lee Dequéanta,1, Delphine Fagegaltierb, Yanhui Hua, Kerstin Spirohna, Amanda Simcoxc, Gregory J. Hannond, and Norbert Perrimona,e,1 aDepartment of Genetics, Harvard Medical School, Boston, MA 02115, bCold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724; cDepartment of Molecular Genetics, The Ohio State University, Columbus, OH 43210; dHoward Hughes Medical Institute, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724; and eHoward Hughes Medical Institute, Harvard Medical School, Boston, MA 02115 Contributed by Norbert Perrimon, September 10, 2015 (sent for review May 18, 2015; reviewed by Peter Cherbas, Gary Karpen, and Renato Paro) The use of time series profiling to identify groups of functionally population contributing to adult muscles (4–7). -
An HMG I/Y-Containing Repressor Complex and Supercolled DNA Topology Are Critical for Long-Range Enhancer-Dependent Transcription in Vitro
Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press An HMG I/Y-containing repressor complex and supercolled DNA topology are critical for long-range enhancer-dependent transcription in vitro Rajesh Bagga and Beverly M. Emerson 1 Regulatory Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037 USA The 3' enhancer of the T cell receptor s.chain (TCR~) gene directs the tissue- and stage-specific expression and V(D)Jrecombination of this gene locus. Using an in vitro system that reproduces TCRoL enhancer activity efficiently, we show that long-range promoter-enhancer regulation requires a T cell-specific repressor complex and is sensitive to DNA topology. In this system, the enhancer functions to derepress the promoter on supercoiled, but not relaxed, templates. We find that the TCRoL promoter is inactivated by a repressor complex that contains the architectural protein HMG I/Y. In the absence of this repressor complex, expression of the TCR~ gene is completely independent of the 3' enhancer and DNA topology. The interaction of the T cell-restricted protein LEF-1 with the TCR~ enhancer is required for promoter derepression. In this system, the TCR~ enhancer increases the number of active promoters rather than the rate of transcription. Thus, long-range enhancers function in a distinct manner from promoters and provide the regulatory link between repressors, DNA topology, and gene activity. [Key Words: TCR genes; transcription; enhancers; HMG I/Y; derepression; DNA topology] Received December 27, 1996; revised version accepted January 14, 1997. The widespread importance of long-range promoter- Giaever 1988; Rippe et al. -
De Novo POGZ Mutations in Sporadic
Matsumura et al. Journal of Molecular Psychiatry (2016) 4:1 DOI 10.1186/s40303-016-0016-x SHORT REPORT Open Access De novo POGZ mutations in sporadic autism disrupt the DNA-binding activity of POGZ Kensuke Matsumura1, Takanobu Nakazawa2*, Kazuki Nagayasu2, Nanaka Gotoda-Nishimura1, Atsushi Kasai1, Atsuko Hayata-Takano1, Norihito Shintani1, Hidenaga Yamamori3, Yuka Yasuda3, Ryota Hashimoto3,4 and Hitoshi Hashimoto1,2,4 Abstract Background: A spontaneous de novo mutation is a new mutation appeared in a child that neither the parent carries. Recent studies suggest that recurrent de novo loss-of-function mutations identified in patients with sporadic autism spectrum disorder (ASD) play a key role in the etiology of the disorder. POGZ is one of the most recurrently mutated genes in ASD patients. Our laboratory and other groups have recently found that POGZ has at least 18 independent de novo possible loss-of-function mutations. Despite the apparent importance, these mutations have never previously been assessed via functional analysis. Methods: Using wild-type, the Q1042R-mutated, and R1008X-mutated POGZ, we performed DNA-binding experiments for proteins that used the CENP-B box sequence in vitro. Data were statistically analyzed by one-way ANOVA followed by Tukey-Kramer post hoc tests. Results: This study reveals that ASD-associated de novo mutations (Q1042R and R1008X) in the POGZ disrupt its DNA-binding activity. Conclusions: Here, we report the first functional characterization of de novo POGZ mutations identified in sporadic ASD cases. These findings provide important insights into the cellular basis of ASD. Keywords: Autism spectrum disorder, Recurrent mutation, De novo mutation, POGZ, DNA-binding activity Background including CHD8, ARID1B, SYNGAP1, DYRK1A, SCN2A, The genetic etiology of autism spectrum disorder (ASD) ANK2, ADNP, DSCAM, CHD2, KDM5B, SUV420H1, remains poorly understood. -
Co-Occupancy by Multiple Cardiac Transcription Factors Identifies
Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart Aibin Hea,b,1, Sek Won Konga,b,c,1, Qing Maa,b, and William T. Pua,b,2 aDepartment of Cardiology and cChildren’s Hospital Informatics Program, Children’s Hospital Boston, Boston, MA 02115; and bHarvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 Edited by Eric N. Olson, University of Texas Southwestern, Dallas, TX, and approved February 23, 2011 (received for review November 12, 2010) Identification of genomic regions that control tissue-specific gene study of a handful of model genes (e.g., refs. 7–10), it has not been expression is currently problematic. ChIP and high-throughput se- evaluated using unbiased, genome-wide approaches. quencing (ChIP-seq) of enhancer-associated proteins such as p300 In this study, we used a modified ChIP-seq approach to define identifies some but not all enhancers active in a tissue. Here we genome wide the binding sites of these cardiac TFs (1). We show that co-occupancy of a chromatin region by multiple tran- provide unbiased support for collaborative TF interactions in scription factors (TFs) identifies a distinct set of enhancers. GATA- driving cardiac gene expression and use this principle to show that chromatin co-occupancy by multiple TFs identifies enhancers binding protein 4 (GATA4), NK2 transcription factor-related, lo- with cardiac activity in vivo. The majority of these multiple TF- cus 5 (NKX2-5), T-box 5 (TBX5), serum response factor (SRF), and “ binding loci (MTL) enhancers were distinct from p300-bound myocyte-enhancer factor 2A (MEF2A), here referred to as cardiac enhancers in location and functional properties. -
Insulators Targets Pcg Proteins to a Downstream Promoter
Developmental Cell 11, 117–124, July, 2006 ª2006 Elsevier Inc. DOI 10.1016/j.devcel.2006.05.009 PRE-Mediated Bypass of Two Short Article Su(Hw) Insulators Targets PcG Proteins to a Downstream Promoter Itys Comet,1 Ekaterina Savitskaya,2,3 dependent on the chromatin surrounding the transgene Bernd Schuettengruber,1 Nicolas Ne`gre,1,4 (barrier activity). Second, when an insulator is placed Sergey Lavrov,1,5 Aleksander Parshikov,2 between an enhancer and a promoter, it can prevent Franc¸ois Juge,1,6 Elena Gracheva,2,7 the enhancer from activating the promoter (enhancer Pavel Georgiev,2,* and Giacomo Cavalli1,* blocking activity). 1 Institute of Human Genetics The Drosophila Su(Hw) insulator, from the gypsy retro- Centre National de la Recherche Scientifique transposon, contains 12 binding sites for the Su(Hw) 141 rue de la Cardonille protein and can block enhancer-promoter interactions F-34396 Montpellier Cedex 5 in a Su(Hw)-dependent manner when inserted between France them (Cai and Levine, 1995; Geyer and Corces, 1992; 2 Department of the Control of Genetic Processes Scott et al., 1999). On the other hand, two intervening Institute of Gene Biology Su(Hw) insulators restore enhancer access to down- Russian Academy of Sciences stream promoters (Cai and Shen, 2001; Muravyova Moscow 119334 et al., 2001). This ability, which is shared by other insula- Russia tor elements (Gruzdeva et al., 2005; Melnikova et al., 2004), was suggested to depend on pairing of the two in- sulators that might bring the upstream enhancer in the Summary vicinity of the downstream promoter. -
Inhibition of Mitochondrial Complex II in Neuronal Cells Triggers Unique
www.nature.com/scientificreports OPEN Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration Sathyanarayanan Ranganayaki1, Neema Jamshidi2, Mohamad Aiyaz3, Santhosh‑Kumar Rashmi4, Narayanappa Gayathri4, Pulleri Kandi Harsha5, Balasundaram Padmanabhan6 & Muchukunte Mukunda Srinivas Bharath7* Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson’s disease, Huntington’s disease and Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) and complex II (CII) by toxins 1‑methyl‑4‑phenylpyridinium (MPP+) and 3‑nitropropionic acid (3‑NPA) respectively, induced degenerative changes noted in such neurodegenerative diseases. We aimed to unravel the down‑stream pathways associated with CII inhibition and compared with CI inhibition and the Manganese (Mn) neurotoxicity. Genome‑wide transcriptomics of N27 neuronal cells exposed to 3‑NPA, compared with MPP+ and Mn revealed varied transcriptomic profle. Along with mitochondrial and synaptic pathways, Autophagy was the predominant pathway diferentially regulated in the 3‑NPA model with implications for neuronal survival. This pathway was unique to 3‑NPA, as substantiated by in silico modelling of the three toxins. Morphological and biochemical validation of autophagy markers in the cell model of 3‑NPA revealed incomplete autophagy mediated by mechanistic Target of Rapamycin Complex 2 (mTORC2) pathway. Interestingly, Brain Derived Neurotrophic Factor -
Appendix 2. Significantly Differentially Regulated Genes in Term Compared with Second Trimester Amniotic Fluid Supernatant
Appendix 2. Significantly Differentially Regulated Genes in Term Compared With Second Trimester Amniotic Fluid Supernatant Fold Change in term vs second trimester Amniotic Affymetrix Duplicate Fluid Probe ID probes Symbol Entrez Gene Name 1019.9 217059_at D MUC7 mucin 7, secreted 424.5 211735_x_at D SFTPC surfactant protein C 416.2 206835_at STATH statherin 363.4 214387_x_at D SFTPC surfactant protein C 295.5 205982_x_at D SFTPC surfactant protein C 288.7 1553454_at RPTN repetin solute carrier family 34 (sodium 251.3 204124_at SLC34A2 phosphate), member 2 238.9 206786_at HTN3 histatin 3 161.5 220191_at GKN1 gastrokine 1 152.7 223678_s_at D SFTPA2 surfactant protein A2 130.9 207430_s_at D MSMB microseminoprotein, beta- 99.0 214199_at SFTPD surfactant protein D major histocompatibility complex, class II, 96.5 210982_s_at D HLA-DRA DR alpha 96.5 221133_s_at D CLDN18 claudin 18 94.4 238222_at GKN2 gastrokine 2 93.7 1557961_s_at D LOC100127983 uncharacterized LOC100127983 93.1 229584_at LRRK2 leucine-rich repeat kinase 2 HOXD cluster antisense RNA 1 (non- 88.6 242042_s_at D HOXD-AS1 protein coding) 86.0 205569_at LAMP3 lysosomal-associated membrane protein 3 85.4 232698_at BPIFB2 BPI fold containing family B, member 2 84.4 205979_at SCGB2A1 secretoglobin, family 2A, member 1 84.3 230469_at RTKN2 rhotekin 2 82.2 204130_at HSD11B2 hydroxysteroid (11-beta) dehydrogenase 2 81.9 222242_s_at KLK5 kallikrein-related peptidase 5 77.0 237281_at AKAP14 A kinase (PRKA) anchor protein 14 76.7 1553602_at MUCL1 mucin-like 1 76.3 216359_at D MUC7 mucin 7, -
Functional Characterization of TBR1 Variants in Neurodevelopmental Disorder Received: 14 May 2018 Joery Den Hoed1, Elliot Sollis1, Hanka Venselaar2, Sara B
www.nature.com/scientificreports OPEN Functional characterization of TBR1 variants in neurodevelopmental disorder Received: 14 May 2018 Joery den Hoed1, Elliot Sollis1, Hanka Venselaar2, Sara B. Estruch1, Pelagia Deriziotis1 & Accepted: 31 August 2018 Simon E. Fisher 1,3 Published: xx xx xxxx Recurrent de novo variants in the TBR1 transcription factor are implicated in the etiology of sporadic autism spectrum disorders (ASD). Disruptions include missense variants located in the T-box DNA- binding domain and previous work has demonstrated that they disrupt TBR1 protein function. Recent screens of thousands of simplex families with sporadic ASD cases uncovered additional T-box variants in TBR1 but their etiological relevance is unclear. We performed detailed functional analyses of de novo missense TBR1 variants found in the T-box of ASD cases, assessing many aspects of protein function, including subcellular localization, transcriptional activity and protein-interactions. Only two of the three tested variants severely disrupted TBR1 protein function, despite in silico predictions that all would be deleterious. Furthermore, we characterized a putative interaction with BCL11A, a transcription factor that was recently implicated in a neurodevelopmental syndrome involving developmental delay and language defcits. Our fndings enhance understanding of molecular functions of TBR1, as well as highlighting the importance of functional testing of variants that emerge from next-generation sequencing, to decipher their contributions to neurodevelopmental disorders like ASD. TBR1 (T-box brain, 1; OMIM *604616) encodes a neuron-specifc transcription factor of the T-box family1. Te TBR1 protein is highly expressed in the deep layers of the cortex, where it is involved in diferentiation of subsets of projection neurons2–4.