Kabuki syndrome stem cell models reveal locus specificity of histone methyltransferase 2D (KMT2D/MLL4)

Human Molecular Genetics, vol. 31, pp. 3715–3728

Abstract

Kabuki syndrome is frequently caused by loss-of-function mutations in one allele of histone 3 lysine 4 (H3K4) methyltransferase KMT2D and is associated with problems in neurological, immunological and skeletal system development. We generated heterozygous KMT2D knockout and Kabuki patient-derived cell models to investigate the role of reduced dosage of KMT2D in stem cells. We discovered chromosomal locus-specific alterations in gene expression, specifically a 110 Kb region containing Synaptotagmin 3 (SYT3), C-Type Lectin Domain Containing 11A (CLEC11A), Chromosome 19 Open Reading Frame 81 (C19ORF81) and SH3 And Multiple Ankyrin Repeat Domains 1 (SHANK1), suggesting locus-specific targeting of KMT2D. Using whole genome histone methylation mapping, we confirmed locus-specific changes in H3K4 methylation patterning coincident with regional decreases in gene expression in Kabuki cell models. Significantly reduced H3K4 peaks aligned with regions of stem cell maps of H3K27 and H3K4 methylation suggesting KMT2D haploinsufficiency impact bivalent enhancers in stem cells. Preparing the genome for subsequent differentiation cues may be of significant importance for Kabuki-related genes. This work provides a new insight into the mechanism of action of an important gene in bone and brain development and may increase our understanding of a specific function of a human disease-relevant H3K4 methyltransferase family member.

Authors 18

1. Malvin Jefri

   McGill University · Douglas Mental Health University Institute

   Affiliation as printed

   Department of Psychiatry , McGill University and Douglas Hospital Research Institute, Montreal, QC H4H 1R3 , Canada

   Psychiatric Genetics Group , McGill University, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Verdun, Montreal, QC H4H 1R3 , Canada

2. Xin Zhang

   McGill University · Douglas Mental Health University Institute

   Affiliation as printed

   Department of Psychiatry , McGill University and Douglas Hospital Research Institute, Montreal, QC H4H 1R3 , Canada

   Psychiatric Genetics Group , McGill University, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Verdun, Montreal, QC H4H 1R3 , Canada

3. Patrick S. Stumpf Aachen Institute for Computational Biomedicine

   RWTH Aachen University

   Affiliation as printed

   Institute for Computational Biomedicine , RWTH Aachen University, Aachen 52056 , Germany

4. Li Zhang

   Johns Hopkins University · Johns Hopkins Medicine

   Affiliation as printed

   McKusick-Nathans Institute of Genetic Medicine , Johns Hopkins University School of Medicine, Baltimore, MD 21205 , USA

5. Huashan Peng

   McGill University · Douglas Mental Health University Institute

   Affiliation as printed

   Department of Psychiatry , McGill University and Douglas Hospital Research Institute, Montreal, QC H4H 1R3 , Canada

   Psychiatric Genetics Group , McGill University, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Verdun, Montreal, QC H4H 1R3 , Canada

6. Nuwan C. Hettige

   McGill University · Douglas Mental Health University Institute

   Affiliation as printed

   Department of Psychiatry , McGill University and Douglas Hospital Research Institute, Montreal, QC H4H 1R3 , Canada

   Psychiatric Genetics Group , McGill University, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Verdun, Montreal, QC H4H 1R3 , Canada

7. Jean‐François Théroux

   McGill University · Douglas Mental Health University Institute

   Affiliation as printed

   Department of Psychiatry , McGill University and Douglas Hospital Research Institute, Montreal, QC H4H 1R3 , Canada

   Psychiatric Genetics Group , McGill University, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Verdun, Montreal, QC H4H 1R3 , Canada

8. Zahia Aouabed

   McGill University · Douglas Mental Health University Institute

   Affiliation as printed

   Department of Psychiatry , McGill University and Douglas Hospital Research Institute, Montreal, QC H4H 1R3 , Canada

   Psychiatric Genetics Group , McGill University, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Verdun, Montreal, QC H4H 1R3 , Canada

9. Khadija Wilson

   Washington University in St. Louis

   Affiliation as printed

   Department of Biochemistry and Molecular , Washington University School of Medicine in St. Louis, St. Louis, MO 63110 , USA

10. Shriya Deshmukh

    McGill University

    Affiliation as printed

    Division of Experimental Medicine , Department of Medicine, McGill University, Montreal, QC H4A 3J1 , Canada

11. Lilit Antonyan

    McGill University · Douglas Mental Health University Institute

    Affiliation as printed

    Department of Psychiatry , McGill University and Douglas Hospital Research Institute, Montreal, QC H4H 1R3 , Canada

    Psychiatric Genetics Group , McGill University, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Verdun, Montreal, QC H4H 1R3 , Canada

12. Anjie Ni

    McGill University · Douglas Mental Health University Institute

    Affiliation as printed

    Department of Psychiatry , McGill University and Douglas Hospital Research Institute, Montreal, QC H4H 1R3 , Canada

    Psychiatric Genetics Group , McGill University, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Verdun, Montreal, QC H4H 1R3 , Canada

13. Shaima Alsuwaidi

    McGill University · Douglas Mental Health University Institute

    Affiliation as printed

    Department of Psychiatry , McGill University and Douglas Hospital Research Institute, Montreal, QC H4H 1R3 , Canada

    Psychiatric Genetics Group , McGill University, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Verdun, Montreal, QC H4H 1R3 , Canada

14. Nada Jabado

    McGill University · McGill University Health Centre · Research Institute of the McGill University Health Centre

    Affiliation as printed

    Department of Human Genetics , McGill University, Montreal, QC H3A 0C7 , Canada

    Department of Pediatrics , McGill University and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1 , Canada

    Division of Experimental Medicine , Department of Medicine, McGill University, Montreal, QC H4A 3J1 , Canada

15. Benjamin Aaron Garcia

    Washington University in St. Louis

    Affiliation as printed

    Department of Biochemistry and Molecular , Washington University School of Medicine in St. Louis, St. Louis, MO 63110 , USA

16. Andreas Schuppert Aachen Institute for Computational Biomedicine

    RWTH Aachen University

    Affiliation as printed

    Institute for Computational Biomedicine , RWTH Aachen University, Aachen 52056 , Germany

17. Hans Tomas Bjornsson

    Johns Hopkins University · Johns Hopkins Medicine · University of Iceland · National University Hospital of Iceland

    Affiliation as printed

    Department of Genetics and Molecular Medicine , Landspitali University Hospital, 101 Reykjavik , Iceland

    Faculty of Medicine , University of Iceland, Reykjavik, Iceland

    McKusick-Nathans Institute of Genetic Medicine , Johns Hopkins University School of Medicine, Baltimore, MD 21205 , USA

18. Carl Ernst corresponding

    McGill University · Douglas Mental Health University Institute

    Affiliation as printed

    Department of Human Genetics , McGill University, Montreal, QC H3A 0C7 , Canada

    Department of Psychiatry , McGill University and Douglas Hospital Research Institute, Montreal, QC H4H 1R3 , Canada

    Psychiatric Genetics Group , McGill University, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Verdun, Montreal, QC H4H 1R3 , Canada