EphrinA5 regulates cell motility by modulating the targeting of DNMT1 to the Ncam1 promoter via lncRNA/DNA triplex formation

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Cell-cell communication is mediated by membrane receptors and their cognate ligands, such as the Eph/ephrin system, and dictates physiological processes, including cell proliferation and migration. However, whether and how Eph/ephrin signaling culminates in transcriptional regulation is largely unknown. Epigenetic mechanisms are key for integrating external “signals”, e.g., from neighboring cells, into the transcriptome. We have previously reported that ephrinA5 stimulation of immortalized cerebellar granule (CB) cells elicits transcriptional changes of lncRNAs and protein-coding genes. LncRNAs represent important adaptors for epigenetic writers through which they regulate gene expression. Here, we investigate the interaction of lncRNA with protein-coding genes by the combined power of in silico modeling of RNA/DNA interactions and respective wet lab approaches, in the context of ephrinA5-dependent regulation of cellular motility. We found that Snhg15 , a cancer-related lncRNA, forms a triplex structure with the Ncam1 promoter and interacts with DNMT1. EphrinA5 stimulation leads to reduced Snhg15 expression, diminished Snhg15 /DNMT1 interaction and decreased DNMT1 association with the Ncam1 promoter. These findings can explain the attenuated Ncam1 promoter methylation and elevated Ncam1 expression that in turn elicits decreased cell motility of CB cells. Hence, we propose that ephrinA5 influences gene transcription via lncRNA-targeted DNA methylation underlying the regulation of cellular motility.

Authors 11

1. Can Bora Yildiz Aachen Division of Neuroepigenetics Institute of Zoology (Biology 2) Research Training Group 416 Multi Senses – Multi Scales

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen University, Institute of Zoology (Biology 2), Division of Neuroepigenetics, Worringerweg 3, 52074 Aachen, Germany

   Research Training Group 2416 Multi Senses – Multi Scales, RWTH Aachen University, 52074 Aachen, Germany

   Research Training Group 416 Multi Senses – Multi Scales, RWTH Aachen University, 5074 Aachen, Germany

2. Tathagata Kundu

   Forschungszentrum Jülich · Jülich Supercomputing Centre

   Affiliation as printed

   Jülich Supercomputing Centre, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany

3. Julia Gehrmann Aachen Institute for Computational Genomics

   RWTH Aachen University

   Affiliation as printed

   Institute for Computational Genomics, RWTH Aachen University, Medical Faculty, 52074 Aachen, Germany

4. Jannis Koesling Aachen Division of Neuroepigenetics Institute of Zoology (Biology 2)

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen University, Institute of Zoology (Biology 2), Division of Neuroepigenetics, Worringerweg 3, 52074 Aachen, Germany

5. Amin Ravaei Aachen Division of Neuroepigenetics Institute of Zoology (Biology 2)

   RWTH Aachen University · University of Ferrara

   Affiliation as printed

   Department of Neurosciences and Rehabilitation, Section of Medical Biochemistry, Molecular Biology and Genetics, University of Ferrara, Italy

   RWTH Aachen University, Institute of Zoology (Biology 2), Division of Neuroepigenetics, Worringerweg 3, 52074 Aachen, Germany

6. Mira Jakovcevski Aachen Division of Neuroepigenetics Institute of Zoology (Biology 2)

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen University, Institute of Zoology (Biology 2), Division of Neuroepigenetics, Worringerweg 3, 52074 Aachen, Germany

7. Daniel Pensold Aachen Division of Neuroepigenetics Institute of Zoology (Biology 2)

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen University, Institute of Zoology (Biology 2), Division of Neuroepigenetics, Worringerweg 3, 52074 Aachen, Germany

8. Olav Zimmermann

   Forschungszentrum Jülich · Jülich Supercomputing Centre

   Affiliation as printed

   Jülich Supercomputing Centre, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany

9. Giulia Rossetti Aachen Department of Neurology

   RWTH Aachen University · Universitätsklinikum Aachen · Forschungszentrum Jülich · Jülich Supercomputing Centre

   Affiliation as printed

   Department of Neurology, University Hospital Aachen, RWTH Aachen University

   Institute of Neuroscience and Medicine (INM-9)/Institute of Advanced simulations (IAS-5), Forschungszentrum Jülich GmbH, 52425 Jülich, Germany

   Jülich Supercomputing Centre, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany

   Institute of Neuroscience and Medicine (INM-9)/Institute of Advanced simulations (IAS-5), Forschungszentrum Jülich GmbH, 5225 Jülich, Germany

10. Ivan G. Costa Aachen Institute for Computational Genomics

    RWTH Aachen University

    Affiliation as printed

    Institute for Computational Genomics, RWTH Aachen University, Medical Faculty, 52074 Aachen, Germany

11. Geraldine Zimmer‐Bensch corresponding Aachen Division of Neuroepigenetics Institute of Zoology (Biology 2) Research Training Group 416 Multi Senses – Multi Scales

    RWTH Aachen University

    Affiliation as printed

    RWTH Aachen University, Institute of Zoology (Biology 2), Division of Neuroepigenetics, Worringerweg 3, 52074 Aachen, Germany

    Research Training Group 2416 Multi Senses – Multi Scales, RWTH Aachen University, 52074 Aachen, Germany

    Research Training Group 416 Multi Senses – Multi Scales, RWTH Aachen University, 5074 Aachen, Germany