SUMOylation differentially regulates SMCHD1 complex formation and function in a genomic context-specific manner

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Structural Maintenance of Chromosomes Hinge Domain Containing 1 (SMCHD1) is a chromatin repressor regulating gene expression and chromatin architecture of distinct autosomal and X-chromosomal loci. SMCHD1 mutations cause derepression of the D4Z4 macrosatellite repeat-embedded DUX4 gene in skeletal muscle of facioscapulohumeral muscular dystrophy (FSHD) patients Little is known about the regulation and post-translational modification of SMCHD1. Here we report the SUMOylation dynamics of SMCHD1 and its impact on autosomal single copy and repetitive loci, and the inactive X chromosome (Xi). We identify that SMCHD1 is SUMOylated primarily at lysine 1374, uncover factors regulating SMCHD1 SUMOylation, and demonstrate that SMCHD1 interacts with chromatin repressors TRIM28, HNRNPK and SETDB1 in a SUMO-dependent manner. We find that SUMOylation impacts Xi engagement of SMCHD1, maintenance of a repressive D4Z4 chromatin structure preventing DUX4 expression, and regulation of LRIF1 promoter activity. The rapid, SUMO-dependent upregulation of DUX4 could explain the bursts of DUX4 expression typical for FSHD muscle.

Authors 10

1. Remko Goossens Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Leiden University Medical Center

2. Mara S. Tihaya Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Leiden University Medical Center

3. Iris M. Willemsen Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Leiden University Medical Center

4. Kirsten R. Straasheijm Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Leiden University Medical Center

5. Patrick J. van der Vliet Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Leiden University Medical Center

6. Román González‐Prieto Aachen

   Leiden University Medical Center · Universidad de Sevilla

   Affiliation as printed

   Leiden University Medical Center / University of Seville

7. Alfred C.O. Vertegaal Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Leiden University Medical Center

8. Stephen J. Tapscott

   Fred Hutch Cancer Center

   Affiliation as printed

   Fred Hutchinson Cancer Center

9. Judit Balog Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center;

   Leiden University Medical Center

10. Silvère M. van der Maarel corresponding Aachen

    Leiden University Medical Center

    Affiliation as printed

    Leiden University Medical Center;

    Leiden University Medical Center