The NSL complex promotes neural development by preventing R-loop induced replication stress

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Summary Early neuronal development relies on the proliferation of neural progenitor cells, making this developmental stage particularly vulnerable to DNA replication impediments. Here, we identify a non-canonical role for the non-specific lethal (NSL) complex in safeguarding DNA replication during neurodevelopment. The NSL complex, which acetylates histone 4 at gene promoters and is mutated in Koolen-de Vries syndrome (KdVS), prevents unscheduled R-loop accumulation at weakly transcribed promoters that are typically devoid of R-loops. Single-cell sequencing reveals that loss of NSL causes replisome stalling and delayed S-phase progression. Neural organoids derived from KdVS patients exhibit impaired DNA replication, developmental abnormalities, and reduced synapse formation, driven entirely by unscheduled R-loop accumulation. These findings reveal that faithful DNA replication is critical for early neurodevelopment.

Authors 21

1. Jolanthe Lingeman Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

2. Diana van den Heuvel Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

3. Jeroen van den Berg

   Royal Netherlands Academy of Arts and Sciences · University Medical Center Utrecht · Oncode Institute · Hubrecht Institute for Developmental Biology and Stem Cell Research

   Affiliation as printed

   Hubrecht Institute;

   Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, Utrecht, The Netherlands

4. Jenny Kaur Singh Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

5. Rosanne van Hooijdonk Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

6. Wouter W. Wiegant Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

7. Daphne E.C. Boer Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

8. Calvin Shun Yu Lo

   Erasmus MC · Erasmus MC Cancer Institute

   Affiliation as printed

   Erasmus University Medical Center;

   Oncode Institute, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

9. Ανδρέας Παναγόπουλος

   University of Zurich

   Affiliation as printed

   University of Zurich;

   Department of Molecular Mechanisms of Disease, University of Zurich (UZH), Zurich, Switzerland

10. Román González‐Prieto Aachen Department of Cell and Chemical Biology

    Leiden University Medical Center

    Affiliation as printed

    Department of Cell and Chemical Biology , Leiden University Medical Center , Leiden , The Netherlands

    Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands

11. Marnix Franken Aachen Department of Human Genetics

    Leiden University Medical Center

    Affiliation as printed

    Leiden University Medical Center;

    Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

12. Nikki Kolsters

    Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour

    Affiliation as printed

    Radboud University Medical Center;

    Department of Human Genetics, Radboud UMC, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands

13. Olivier G. de Jong

    Utrecht University

    Affiliation as printed

    Utrecht University

    Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands

14. Alfred C.O. Vertegaal Aachen Department of Cell and Chemical Biology

    Leiden University Medical Center

    Affiliation as printed

    Leiden University Medical Center;

    Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands

15. Matthias Altmeyer

    University of Zurich

    Affiliation as printed

    University of Zurich;

    Department of Molecular Mechanisms of Disease, University of Zurich (UZH), Zurich, Switzerland

16. Nitika Taneja

    Erasmus MC · Erasmus MC Cancer Institute

    Affiliation as printed

    Erasmus University Medical Center;

    Oncode Institute, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

17. Alexander van Oudenaarden

    Royal Netherlands Academy of Arts and Sciences · University Medical Center Utrecht · Oncode Institute · Hubrecht Institute for Developmental Biology and Stem Cell Research

    Affiliation as printed

    Hubrecht Institute;

    Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, Utrecht, The Netherlands

18. Martijn S. Luijsterburg Aachen Department of Human Genetics

    Leiden University Medical Center

    Affiliation as printed

    Leiden University Medical Center;

    Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

19. Nael Nadif Kasri

    Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour

    Affiliation as printed

    Radboud University Medical Center;

    Department of Human Genetics, Radboud UMC, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands

20. Brooke L. Latour corresponding

    Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour

    Affiliation as printed

    Radboud University Medical Center;

    Department of Human Genetics, Radboud UMC, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands

21. Haico van Attikum Aachen Department of Human Genetics

    Leiden University Medical Center

    Affiliation as printed

    Leiden University Medical Center;

    Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands