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ZFP462 targets heterochromatin to transposon-derived enhancers restricting transcription factor binding and expression of lineage-specifying genes

View ORCID ProfileRamesh Yelagandula, Karin Stecher, View ORCID ProfileMaria Novatchkova, View ORCID ProfileLuca Michetti, View ORCID ProfileGeorg Michlits, View ORCID ProfileJingkui Wang, Pablo Hofbauer, Carina Pribitzer, Gintautas Vainorius, View ORCID ProfileLuke Isbel, View ORCID ProfileSasha Mendjan, Dirk Schübeler, View ORCID ProfileUlrich Elling, View ORCID ProfileJulius Brennecke, View ORCID ProfileOliver Bell
doi: https://doi.org/10.1101/2021.06.28.449463
Ramesh Yelagandula
1Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, Vienna BioCenter (VBC), Vienna, Austria
4Department of Biochemistry and Molecular Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90089, USA
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  • ORCID record for Ramesh Yelagandula
  • For correspondence: ramesh.yelagandula@imba.oeaw.ac.at oliver.bell@med.usc.edu
Karin Stecher
1Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, Vienna BioCenter (VBC), Vienna, Austria
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Maria Novatchkova
1Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, Vienna BioCenter (VBC), Vienna, Austria
2Research Institute of Molecular Pathology (IMP), Campus-Vienna-BioCenter 1, Vienna BioCenter (VBC), Vienna, Austria
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Luca Michetti
1Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, Vienna BioCenter (VBC), Vienna, Austria
5Università Vita-Salute San Raffaele, via Olgettina 58, 20132 Milan, Italy
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Georg Michlits
1Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, Vienna BioCenter (VBC), Vienna, Austria
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Jingkui Wang
2Research Institute of Molecular Pathology (IMP), Campus-Vienna-BioCenter 1, Vienna BioCenter (VBC), Vienna, Austria
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Pablo Hofbauer
1Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, Vienna BioCenter (VBC), Vienna, Austria
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Carina Pribitzer
2Research Institute of Molecular Pathology (IMP), Campus-Vienna-BioCenter 1, Vienna BioCenter (VBC), Vienna, Austria
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Gintautas Vainorius
1Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, Vienna BioCenter (VBC), Vienna, Austria
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Luke Isbel
3Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
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Sasha Mendjan
1Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, Vienna BioCenter (VBC), Vienna, Austria
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Dirk Schübeler
3Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
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Ulrich Elling
1Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, Vienna BioCenter (VBC), Vienna, Austria
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Julius Brennecke
1Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, Vienna BioCenter (VBC), Vienna, Austria
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Oliver Bell
1Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, Vienna BioCenter (VBC), Vienna, Austria
4Department of Biochemistry and Molecular Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90089, USA
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  • For correspondence: ramesh.yelagandula@imba.oeaw.ac.at oliver.bell@med.usc.edu
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Abstract

ZNF462 haploinsufficiency is linked to Weiss-Kruszka Syndrome, a genetic disorder characterized by a range of neurodevelopmental defects including Autism. Though it is highly conserved in vertebrates and essential for embryonic development the molecular functions of ZNF462 are unclear. We identified its murine homolog ZFP462 in a screen for epigenetic gene silencing in mouse embryonic stem cells (mESCs). Here, we show ZFP462 safeguards neural lineage specification by targeting the H3K9-specific histone methyltransferase complex G9A/GLP to mediate epigenetic silencing of endodermal genes. ZFP462 binds to thousands of transposable elements (TEs) that harbor ESC- and endoderm-specific transcription factor (TF) binding sites and act as enhancers. Through physical interaction with G9A/GLP, ZFP462 seeds heterochromatin at TE-derived enhancers restricting the binding of core pluripotency TFs OCT4 and SOX2. Loss of ZFP462 in ESCs results in increased chromatin accessibility at target sites and ectopic expression of endodermal genes. Taken together, ZFP462 restricts TF binding and subsequent endodermspecific gene activation by conferring lineage and locus-specificity to the broadly expressed epigenetic regulator G9A/GLP. Our results suggest that aberrant activation of endodermal genes in the neuronal lineage underlies ZNF462-associated neurodevelopmental pathology.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵6 Co-first author

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 28, 2021.
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ZFP462 targets heterochromatin to transposon-derived enhancers restricting transcription factor binding and expression of lineage-specifying genes
Ramesh Yelagandula, Karin Stecher, Maria Novatchkova, Luca Michetti, Georg Michlits, Jingkui Wang, Pablo Hofbauer, Carina Pribitzer, Gintautas Vainorius, Luke Isbel, Sasha Mendjan, Dirk Schübeler, Ulrich Elling, Julius Brennecke, Oliver Bell
bioRxiv 2021.06.28.449463; doi: https://doi.org/10.1101/2021.06.28.449463
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ZFP462 targets heterochromatin to transposon-derived enhancers restricting transcription factor binding and expression of lineage-specifying genes
Ramesh Yelagandula, Karin Stecher, Maria Novatchkova, Luca Michetti, Georg Michlits, Jingkui Wang, Pablo Hofbauer, Carina Pribitzer, Gintautas Vainorius, Luke Isbel, Sasha Mendjan, Dirk Schübeler, Ulrich Elling, Julius Brennecke, Oliver Bell
bioRxiv 2021.06.28.449463; doi: https://doi.org/10.1101/2021.06.28.449463

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