Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs

Alessa R. Ringel, Quentin Szabo, Andrea M. Chiariello, Konrad Chudzik, Robert Schöpflin, Patricia Rothe, Alexandra L. Mattei, Tobias Zehnder, Dermot Harnett, Verena Laupert, Simona Bianco, Sara Hetzel, Mai Phan, Magdalena Schindler, Daniel Ibrahim, Christina Paliou, Andrea Esposito, Cesar A. Prada-Medina, Stefan Haas, Peter Giere, Martin Vingron, Lars Wittler, Alexander Meissner, Mario Nicodemi, Giacomo Cavalli, Frédéric Bantignies, Stefan Mundlos, Michael I. Robson
doi: https://doi.org/10.1101/2021.10.08.463672
Alessa R. Ringel
1Max Planck Institute for Molecular Genetics, Berlin, Germany
2Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Germany
3Institute of Chemistry and Biochemistry, Freie Universität Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Quentin Szabo
4Institute of Human Genetics, Centre National de la Recherche Scientifique, University of Montpellier, Montpellier, France
5Institute of Molecular Sciences, University of Zurich, Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrea M. Chiariello
6Dipartimento di Fisica, Università di Napoli Federico II and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, Naples, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Konrad Chudzik
1Max Planck Institute for Molecular Genetics, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert Schöpflin
1Max Planck Institute for Molecular Genetics, Berlin, Germany
2Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patricia Rothe
1Max Planck Institute for Molecular Genetics, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alexandra L. Mattei
1Max Planck Institute for Molecular Genetics, Berlin, Germany
7Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA
8Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tobias Zehnder
1Max Planck Institute for Molecular Genetics, Berlin, Germany
2Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dermot Harnett
9Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Verena Laupert
1Max Planck Institute for Molecular Genetics, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Simona Bianco
6Dipartimento di Fisica, Università di Napoli Federico II and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, Naples, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sara Hetzel
1Max Planck Institute for Molecular Genetics, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mai Phan
1Max Planck Institute for Molecular Genetics, Berlin, Germany
10Charité-Universitätsmedizin Berlin, BCRT-Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Magdalena Schindler
1Max Planck Institute for Molecular Genetics, Berlin, Germany
2Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel Ibrahim
10Charité-Universitätsmedizin Berlin, BCRT-Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
1Max Planck Institute for Molecular Genetics, Berlin, Germany
2Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christina Paliou
11Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Seville, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrea Esposito
6Dipartimento di Fisica, Università di Napoli Federico II and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, Naples, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cesar A. Prada-Medina
12Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
1Max Planck Institute for Molecular Genetics, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefan Haas
1Max Planck Institute for Molecular Genetics, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter Giere
13Museum für Naturkunde, Leibniz Institute for Research on Evolution and Biodiversity, Humboldt University Berlin, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Vingron
1Max Planck Institute for Molecular Genetics, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lars Wittler
1Max Planck Institute for Molecular Genetics, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alexander Meissner
1Max Planck Institute for Molecular Genetics, Berlin, Germany
3Institute of Chemistry and Biochemistry, Freie Universität Berlin, Germany
8Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
14Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mario Nicodemi
6Dipartimento di Fisica, Università di Napoli Federico II and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, Naples, Italy
9Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Giacomo Cavalli
4Institute of Human Genetics, Centre National de la Recherche Scientifique, University of Montpellier, Montpellier, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frédéric Bantignies
4Institute of Human Genetics, Centre National de la Recherche Scientifique, University of Montpellier, Montpellier, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefan Mundlos
1Max Planck Institute for Molecular Genetics, Berlin, Germany
2Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Germany
10Charité-Universitätsmedizin Berlin, BCRT-Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: mundlos@molgen.mpg.de robson@molgen.mpg.de
Michael I. Robson
1Max Planck Institute for Molecular Genetics, Berlin, Germany
2Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Germany
15Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: mundlos@molgen.mpg.de robson@molgen.mpg.de
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

SUMMARY

Cohesin loop extrusion facilitates precise gene expression by continuously driving promoters to sample all enhancers located within the same topologically-associated domain (TAD). However, many TADs contain multiple genes with divergent expression patterns, thereby indicating additional forces further refine how enhancer activities are utilised. Here, we unravel the mechanisms enabling a new gene, Rex1, to emerge with divergent expression within the ancient Fat1 TAD in placental mammals. We show that such divergent expression is not determined by a strict enhancer-promoter compatibility code, intra-TAD position or nuclear envelope-attachment. Instead, TAD-restructuring in embryonic stem cells (ESCs) separates Rex1 and Fat1 with distinct proximal enhancers that independently drive their expression. By contrast, in later embryonic tissues, DNA methylation renders the inactive Rex1 promoter profoundly unresponsive to Fat1 enhancers within the intact TAD. Combined, these features adapted an ancient regulatory landscape during evolution to support two entirely independent Rex1 and Fat1 expression programs. Thus, rather than operating only as rigid blocks of co-regulated genes, TAD-regulatory landscapes can orchestrate complex divergent expression patterns in evolution.

HIGHLIGHTS

  • New genes can emerge in evolution without taking on the expression pattern of their surrounding pre-existing TAD.

  • Compartmentalisation can restructure seemingly evolutionarily stable TADs to control a promoter’s access to enhancers.

  • Lamina-associated domains neither prevent transcriptional activation nor enhancer-promoter communication.

  • Repression rather than promoter-specificity refines when genes respond to promiscuous enhancer activities in specific tissues.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted October 09, 2021.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs
Alessa R. Ringel, Quentin Szabo, Andrea M. Chiariello, Konrad Chudzik, Robert Schöpflin, Patricia Rothe, Alexandra L. Mattei, Tobias Zehnder, Dermot Harnett, Verena Laupert, Simona Bianco, Sara Hetzel, Mai Phan, Magdalena Schindler, Daniel Ibrahim, Christina Paliou, Andrea Esposito, Cesar A. Prada-Medina, Stefan Haas, Peter Giere, Martin Vingron, Lars Wittler, Alexander Meissner, Mario Nicodemi, Giacomo Cavalli, Frédéric Bantignies, Stefan Mundlos, Michael I. Robson
bioRxiv 2021.10.08.463672; doi: https://doi.org/10.1101/2021.10.08.463672
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs
Alessa R. Ringel, Quentin Szabo, Andrea M. Chiariello, Konrad Chudzik, Robert Schöpflin, Patricia Rothe, Alexandra L. Mattei, Tobias Zehnder, Dermot Harnett, Verena Laupert, Simona Bianco, Sara Hetzel, Mai Phan, Magdalena Schindler, Daniel Ibrahim, Christina Paliou, Andrea Esposito, Cesar A. Prada-Medina, Stefan Haas, Peter Giere, Martin Vingron, Lars Wittler, Alexander Meissner, Mario Nicodemi, Giacomo Cavalli, Frédéric Bantignies, Stefan Mundlos, Michael I. Robson
bioRxiv 2021.10.08.463672; doi: https://doi.org/10.1101/2021.10.08.463672

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genetics
Subject Areas
All Articles
  • Animal Behavior and Cognition (4685)
  • Biochemistry (10362)
  • Bioengineering (7682)
  • Bioinformatics (26342)
  • Biophysics (13534)
  • Cancer Biology (10693)
  • Cell Biology (15446)
  • Clinical Trials (138)
  • Developmental Biology (8501)
  • Ecology (12824)
  • Epidemiology (2067)
  • Evolutionary Biology (16867)
  • Genetics (11401)
  • Genomics (15484)
  • Immunology (10619)
  • Microbiology (25225)
  • Molecular Biology (10225)
  • Neuroscience (54481)
  • Paleontology (402)
  • Pathology (1669)
  • Pharmacology and Toxicology (2897)
  • Physiology (4345)
  • Plant Biology (9252)
  • Scientific Communication and Education (1587)
  • Synthetic Biology (2558)
  • Systems Biology (6781)
  • Zoology (1466)