Research Group Dr. Phillip Grote
The role of long, non-protein coding RNAs (lncRNAs) in gene and genome regulation
The genome encodes all the information required to direct the development of an organism from the fertilized egg into a complex human organism. Mis-regulation in these gene programs can lead to cancer, in children and adults. A novel class of genes, the long, non-protein coding RNAs (lncRNAs) and their role in gene and genome regulation are receiving increased attention as potential therapeutic targets to control gene and genome activity and reverse such mis-regulated gene programs.
LncRNA genes produce RNA molecules as any protein coding gene, but the RNA is not getting translated into larger peptides or proteins. Instead, either the RNA itself serves a biomolecule and interacts with other components in a cell such as DNA, RNA or proteins, or the process of generating the RNA itself already is functional with respect to gene and genome activity. While initially such lncRNA genes were disregarded as noise, in recent years several labs around the world could show that lncRNA genes actually can have important functions for the organism. In addition, deep profiling of all RNA species in cells and tissues by next generation sequencing, led to discovery that almost as many lncRNA genes are embedded in the human genome as protein coding genes. This led to fascinating research in how such lncRNA genes can actually exert their function and how novel anti-sense based drug approaches can amend their function for a beneficially outcome in various genetic diseases.
Function of lncRNAs in oncology
Our research pioneered the genetic analysis of lncRNA function in a whole organism context. We discovered that the two lncRNA genes Fendrr and Handsdown are essential for the organism and in particular for regulating specific gene programs. While our genetic approach defined that Fendrr acts on the RNA level, we show that the Handsdown lncRNA locus exerts its function via its transcription. We are focused previously at developmental gene programs in the cardiac system and are expanding our research, towards the role of lncRNAs in oncology. In particular the gene programs regulated by the above mentioned two lncRNA genes are also involved in small lung cell cancer and endometrial cancer, respectively.
We are using mouse models to understand the function of lncRNAs in an organismal and disease context, thereby understanding more about genome regulation by lncRNAs and exploring potential drug targets for intervention.
Team
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
More Publications
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…
