Forschungsgruppe Dr. Phillip Grote
Die Rolle langer, nicht-proteinkodierender RNAs (lncRNAs) in der Gen- und Genomregulierung
Das Genom kodiert alle Informationen, die erforderlich sind, um die Entwicklung eines Organismus von der befruchteten Eizelle bis zum komplexen menschlichen Organismus zu steuern. Fehlregulationen im Genprogramm können bei Kindern und Erwachsenen zu Krebs führen. Eine neue Klasse von Genen, die langen, nicht-proteinkodierenden RNAs (lncRNAs) und ihre Rolle bei der Gen- und Genomregulierung erhalten zunehmende Aufmerksamkeit als potenzielle therapeutische Angriffspunkte zur Kontrolle der Gen- und Genomaktivität und zur Umkehrung solcher fehlregulierten Genprogramme.
LncRNA-Gene produzieren RNA-Moleküle, genauso wie alle proteinkodierenden Gene, aber die RNA wird nicht in größere Peptide oder Proteine übersetzt. Stattdessen dient entweder die RNA selbst als Biomolekül und interagiert mit anderen Komponenten in einer Zelle wie DNA, RNA oder Proteinen, oder der Prozess der RNA-Erzeugung selbst ist bereits funktionell in Bezug auf die Gen- und Genomaktivität. Während solche lncRNA-Gene zunächst als Rauschen abgetan wurden, konnten in den letzten Jahren mehrere Labore weltweit zeigen, dass lncRNA-Gene tatsächlich wichtige Funktionen für den Organismus haben können. Darüber hinaus führte die ausführliche Detektion von allen RNA-Spezies in Zellen und Geweben durch Hochdurchsatz Sequenzierung zu der Entdeckung, dass fast ebenso viele lncRNA-Gene in das menschliche Genom eingebettet sind wie proteinkodierende Gene. Dies führte zu faszinierenden Forschungen: wie üben solche lncRNA-Gene ihre Funktion tatsächlich aus und wie können neuartige, auf Antisense basierende Arzneimittelansätze deren Funktion ändern, um so bei verschiedenen genetischen Krankheiten einen positiven Effekt zu erzielen.
Funktion der lncRNAs in der Onkologie
Unsere Forschung leistete Pionierarbeit bei der genetischen Analyse von lncRNA-Funktionen im Kontext des gesamten Organismus. Wir entdeckten, dass die beiden lncRNA-Gene Fendrr und Handsdown für den Organismus und insbesondere für die Regulierung spezifischer Genprogramme wichtig sind. Während unser genetischer Ansatz definiert, dass Fendrr auf der RNA-Ebene agiert, zeigen wir, dass der lncRNA-Lokus Handsdown seine Funktion über seine Transkription ausübt. Wir haben uns bisher auf entwicklungsbedingte Genprogramme im Herzsystem konzentriert und weiten unsere Forschung auf die Rolle von lncRNAs in der Onkologie aus. Vor allem die Genprogramme, die von den beiden oben genannten lncRNA-Genen reguliert werden, sind ebenfalls bei kleinen Lungenzellkarzinomen, bzw. im Endometriumkrebs involviert.
Wir verwenden Mausmodelle, um die Funktion von lncRNAs in einem organismischen und krankheitsbezogenen Kontext zu verstehen und dadurch mehr über die Genomregulierung durch lncRNAs zu erfahren und potenzielle Angriffspunkte für Medikamente zu erkunden.
Ausgewählte Publikationen
Rogala, S., Ali, T., Melissari, M.-T., Waehrisch, S., Schuster, P., Sarre, A., Boettger, T., Rogg, E.-M., Kaur, J., Krishnan, J., Dimmeler, S., Ounzain, S., Pedrazzini, Th., Herrmann, B.G. and Grote, P. (2023).
The lncRNA Sweetheart regulates compensatory cardiac hypertrophy after myocardial injury in murine males.
Nat Commun, 14, 7024. 10.1038/s41467-023-42760-y.
Ali, T., Rogala, S., Krause, N.M., Bains, J.K., Melissari, M.T., Wahrisch, S., Schwalbe, H., Herrmann, B.G., and Grote, P. (2023).
Fendrr synergizes with Wnt signalling to regulate fibrosis related genes during lung development via its RNA:dsDNA triplex element.
NucleicAcidsRes. 10.1093/nar/gkad395.
Ali, T., & Grote, P. (2020).
Beyond the RNA-dependent function of LncRNA genes.
ELife, 9. doi.org/10.7554/eLife.60583
Ritter, N., Ali, T., Kopitchinski, N., Schuster, P., Beisaw, A., Hendrix, D. A., Schulz, M. H., Müller-McNicoll, M., Dimmeler, S., & Grote, P. (2019).
The lncRNA Locus Handsdown Regulates Cardiac Gene Programs and Is Essential for Early Mouse Development.
Developmental Cell, 50(5), 644-657.e8. doi.org/10.1016/j.devcel.2019.07.013
Weitere Publikationen
A Chemically Induced CRISPR/dCas13FCPF Platform for Precise and Programmable RNA Regulation
J Med Chem. 2025 Nov 13;68(21):22633-22649. doi: 10.1021/acs.jmedchem.5c01609. Epub 2025 Oct 22.
ABSTRACT
Alternative splicing enhances proteomic diversity, yet its…
Biophysical Investigation of RNA ⋅ DNA : DNA Triple Helix and RNA : DNA Heteroduplex Formation by the lncRNAs MEG3 and Fendrr
Chembiochem. 2024 May 17;25(10):e202400049. doi: 10.1002/cbic.202400049. Epub 2024 Apr 29.
ABSTRACT
Long non-coding RNAs (lncRNAs) are important regulators of gene…
Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies
NPJ Genom Med. 2024 Mar 1;9(1):18. doi: 10.1038/s41525-024-00398-9.
ABSTRACT
CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals…
The lncRNA Sweetheart regulates compensatory cardiac hypertrophy after myocardial injury in murine males
Nat Commun. 2023 Nov 2;14(1):7024. doi: 10.1038/s41467-023-42760-y.
ABSTRACT
After myocardial infarction in the adult heart the remaining, non-infarcted tissue adapts to…
Fendrr synergizes with Wnt signalling to regulate fibrosis related genes during lung development via its RNA:dsDNA triplex element
Nucleic Acids Res. 2023 Jul 7;51(12):6227-6237. doi: 10.1093/nar/gkad395.
ABSTRACT
Long non-coding RNAs are a very versatile class of molecules that can have important…
Retinoic acid signaling modulation guides in vitro specification of human heart field-specific progenitor pools
Nat Commun. 2023 Apr 3;14(1):1722. doi: 10.1038/s41467-023-36764-x.
ABSTRACT
Cardiogenesis relies on the precise spatiotemporal coordination of multiple progenitor…
X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems
J Med Genet. 2023 Jun;60(6):587-596. doi: 10.1136/jmg-2022-108738. Epub 2022 Nov 15.
ABSTRACT
BACKGROUND: SHROOM4 is thought to play an important role in cytoskeletal…
Genome-wide identification of disease-causing copy number variations in 450 individuals with anorectal malformations
Eur J Hum Genet. 2023 Jan;31(1):105-111. doi: 10.1038/s41431-022-01216-5. Epub 2022 Nov 1.
ABSTRACT
Anorectal malformations (ARM) represent a spectrum of rare…
First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B
HGG Adv. 2022 Jan 25;3(2):100093. doi: 10.1016/j.xhgg.2022.100093. eCollection 2022 Apr 14.
ABSTRACT
Esophageal atresia with or without tracheoesophageal fistula…
Locus-Conserved Circular RNA cZNF292 Controls Endothelial Cell Flow Responses
Circ Res. 2022 Jan 7;130(1):67-79. doi: 10.1161/CIRCRESAHA.121.320029. Epub 2021 Nov 18.
ABSTRACT
BACKGROUND: Circular RNAs (circRNAs) are generated by back splicing of…
Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator
Nature. 2021 Apr;592(7852):93-98. doi: 10.1038/s41586-021-03208-9. Epub 2021 Feb 10.
ABSTRACT
Long non-coding RNAs (lncRNAs) can be important components in…
Beyond the RNA-dependent function of LncRNA genes
Elife. 2020 Oct 23;9:e60583. doi: 10.7554/eLife.60583.
ABSTRACT
While long non-coding RNA (lncRNA) genes have attracted a lot of attention in the last decade, the focus…
SLC20A1 Is Involved in Urinary Tract and Urorectal Development
Front Cell Dev Biol. 2020 Aug 7;8:567. doi: 10.3389/fcell.2020.00567. eCollection 2020.
ABSTRACT
Previous studies in developing Xenopus and zebrafish reported that the…
Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia
PLoS One. 2020 Jun 5;15(6):e0234246. doi: 10.1371/journal.pone.0234246. eCollection 2020.
ABSTRACT
INTRODUCTION: Esophageal atresia with or without tracheoesophageal…
The lncRNA Locus Handsdown Regulates Cardiac Gene Programs and Is Essential for Early Mouse Development
Dev Cell. 2019 Sep 9;50(5):644-657.e8. doi: 10.1016/j.devcel.2019.07.013. Epub 2019 Aug 15.
ABSTRACT
Precisely controlled gene regulatory networks are required during…
Signals trigger state-specific transcriptional programs to support diversity and homeostasis in immune cells
Sci Signal. 2019 May 14;12(581):eaao5820. doi: 10.1126/scisignal.aao5820.
ABSTRACT
Macrophages play key roles in the immune systems of humans and other mammals. Here, we…
Rare Variants in BNC2 Are Implicated in Autosomal-Dominant Congenital Lower Urinary-Tract Obstruction
Am J Hum Genet. 2019 May 2;104(5):994-1006. doi: 10.1016/j.ajhg.2019.03.023.
ABSTRACT
Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage…
Inhibition of the Hypoxia-Inducible Factor 1α-Induced Cardiospecific HERNA1 Enhance-Templated RNA Protects From Heart Disease
Circulation. 2019 Jun 11;139(24):2778-2792. doi: 10.1161/CIRCULATIONAHA.118.036769. Epub 2019 Mar 29.
ABSTRACT
BACKGROUND: Enhancers are genomic regulatory elements…
LncRNAs Coming of Age
Circ Res. 2018 Aug 17;123(5):535-537. doi: 10.1161/CIRCRESAHA.118.313447.
NO ABSTRACT
PMID:30355139 | DOI:10.1161/CIRCRESAHA.118.313447
The lncRNA GATA6-AS epigenetically regulates endothelial gene expression via interaction with LOXL2
Nat Commun. 2018 Jan 16;9(1):237. doi: 10.1038/s41467-017-02431-1.
ABSTRACT
Impaired or excessive growth of endothelial cells contributes to several diseases. However,…
BRACHYURY directs histone acetylation to target loci during mesoderm development
EMBO Rep. 2018 Jan;19(1):118-134. doi: 10.15252/embr.201744201. Epub 2017 Nov 15.
ABSTRACT
T-box transcription factors play essential roles in multiple aspects of…
Antagonistic Activities of Sox2 and Brachyury Control the Fate Choice of Neuro-Mesodermal Progenitors
Dev Cell. 2017 Sep 11;42(5):514-526.e7. doi: 10.1016/j.devcel.2017.07.021. Epub 2017 Aug 17.
ABSTRACT
The spinal cord and mesodermal tissues of the trunk such as the…
Identification and Functional Characterization of Hypoxia-Induced Endoplasmic Reticulum Stress Regulating lncRNA (HypERlnc) in Pericytes
Circ Res. 2017 Aug 4;121(4):368-375. doi: 10.1161/CIRCRESAHA.116.310531. Epub 2017 Jun 13.
ABSTRACT
RATIONALE: Pericytes are essential for vessel maturation and…
Different Concentrations of FGF Ligands, FGF2 or FGF8 Determine Distinct States of WNT-Induced Presomitic Mesoderm
Stem Cells. 2016 Jul;34(7):1790-800. doi: 10.1002/stem.2371. Epub 2016 Apr 18.
ABSTRACT
Presomitic mesoderm (PSM) cells are the precursors of the somites, which flank…
Mechanisms of long noncoding RNA function in development and disease
Cell Mol Life Sci. 2016 Jul;73(13):2491-509. doi: 10.1007/s00018-016-2174-5. Epub 2016 Mar 23.
ABSTRACT
Since decades it has been known that non-protein-coding RNAs have…
Roles for long non-coding RNAs in physiology and disease
Pflugers Arch. 2016 Jun;468(6):945-58. doi: 10.1007/s00424-016-1804-y. Epub 2016 Mar 5.
ABSTRACT
While the vast majority of the genome is transcribed into RNA, only a…
Analysis of the Fam181 gene family during mouse development reveals distinct strain-specific expression patterns, suggesting a role in nervous system development and function
Gene. 2016 Jan 10;575(2 Pt 2):438-451. doi: 10.1016/j.gene.2015.09.035. Epub 2015 Sep 25.
ABSTRACT
During somitogenesis differential gene expression can be observed for…
Long noncoding RNAs in organogenesis: making the difference
Trends Genet. 2015 Jun;31(6):329-35. doi: 10.1016/j.tig.2015.02.002. Epub 2015 Mar 2.
ABSTRACT
A large proportion of the cellular transcriptome of higher vertebrates…
SRF is essential for mesodermal cell migration during elongation of the embryonic body axis
Mech Dev. 2014 Aug;133:23-35. doi: 10.1016/j.mod.2014.07.001. Epub 2014 Jul 11.
ABSTRACT
Mesoderm formation in the mouse embryo initiates around E6.5 at the primitive…
The tissue-specific transcriptomic landscape of the mid-gestational mouse embryo
Development. 2014 Jun;141(11):2325-30. doi: 10.1242/dev.105858. Epub 2014 May 6.
ABSTRACT
Differential gene expression is a prerequisite for the formation of multiple…
Dlk1 promotes a fast motor neuron biophysical signature required for peak force execution
Science. 2014 Mar 14;343(6176):1264-6. doi: 10.1126/science.1246448.
ABSTRACT
Motor neurons, which relay neural commands to drive skeletal muscle movements, encompass…
Tpo1-mediated spermine and spermidine export controls cell cycle delay and times antioxidant protein expression during the oxidative stress response
EMBO Rep. 2013 Dec;14(12):1113-9. doi: 10.1038/embor.2013.165. Epub 2013 Oct 18.
ABSTRACT
Cells counteract oxidative stress by altering metabolism, cell cycle and gene…
The long non-coding RNA Fendrr links epigenetic control mechanisms to gene regulatory networks in mammalian embryogenesis
RNA Biol. 2013 Oct;10(10):1579-85. doi: 10.4161/rna.26165. Epub 2013 Aug 22.
ABSTRACT
Epigenetic control mechanisms determine active and silenced regions of the genome.…
DNA-methylome analysis of mouse intestinal adenoma identifies a tumour-specific signature that is partly conserved in human colon cancer
PLoS Genet. 2013;9(2):e1003250. doi: 10.1371/journal.pgen.1003250. Epub 2013 Feb 7.
ABSTRACT
Aberrant CpG methylation is a universal epigenetic trait of cancer cell…
The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse
Dev Cell. 2013 Jan 28;24(2):206-14. doi: 10.1016/j.devcel.2012.12.012.
ABSTRACT
The histone-modifying complexes PRC2 and TrxG/MLL play pivotal roles in determining the…
An inducible RNA interference system for the functional dissection of mouse embryogenesis
Nucleic Acids Res. 2010 Jun;38(11):e122. doi: 10.1093/nar/gkq199. Epub 2010 Mar 28.
ABSTRACT
Functional analysis of multiple genes is key to understanding gene…
Expression of Msgn1 in the presomitic mesoderm is controlled by synergism of WNT signalling and Tbx6
EMBO Rep. 2007 Aug;8(8):784-9. doi: 10.1038/sj.embor.7401030. Epub 2007 Jul 13.
ABSTRACT
The vertebral column and skeletal muscles of vertebrates are derived from the…
The PLZF-like protein TRA-4 cooperates with the Gli-like transcription factor TRA-1 to promote female development in C. elegans
Dev Cell. 2006 Oct;11(4):561-73. doi: 10.1016/j.devcel.2006.07.015.
ABSTRACT
The Gli-like transcription factor TRA-1 of C. elegans promotes female development by…
DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans
Nature. 2005 Feb 17;433(7027):754-60. doi: 10.1038/nature03316.
ABSTRACT
Genetic analyses in Caenorhabditis elegans have been instrumental in the elucidation of the…
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