title: Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation.
abstract: Structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is an epigenetic repressor with described roles in X inactivation and genomic imprinting, but Smchd1 is also critically involved in the pathogenesis of facioscapulohumeral dystrophy. The underlying molecular mechanism by which Smchd1 functions in these instances remains unknown. Our genome-wide transcriptional and epigenetic analyses show that Smchd1 binds cis-regulatory elements, many of which coincide with CCCTC-binding factor (Ctcf) binding sites, for example, the clustered protocadherin (Pcdh) genes, where we show Smchd1 and Ctcf act in opposing ways. We provide biochemical and biophysical evidence that Smchd1-chromatin interactions are established through the homodimeric hinge domain of Smchd1 and, intriguingly, that the hinge domain also has the capacity to bind DNA and RNA. Our results suggest Smchd1 imparts epigenetic regulation via physical association with chromatin, which may antagonize Ctcf-facilitated chromatin interactions, resulting in coordinated transcriptional control.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia;
authors.forename: Kelan
authors.initials: K
authors.lastname: Chen
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Institute of Health and Biomedical Innovation, School of Biomolecular Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4000, Australia;
authors.forename: Jiang
authors.initials: J
authors.lastname: Hu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia;
authors.forename: Darcy L
authors.initials: DL
authors.lastname: Moore
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia;
authors.forename: Ruijie
authors.initials: R
authors.lastname: Liu
authors.affiliation: Biomolecular Interaction Centre and School of Biological Sciences, University of Canterbury, Christchurch, Private Bag 4800, New Zealand;
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Kessans
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia;
authors.forename: Kelsey
authors.initials: K
authors.lastname: Breslin
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia;
authors.forename: Isabelle S
authors.initials: IS
authors.lastname: Lucet
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia;
authors.forename: Andrew
authors.initials: A
authors.lastname: Keniry
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia;
authors.forename: Huei San
authors.initials: HS
authors.lastname: Leong
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC 3010, Australia;
authors.forename: Clare L
authors.initials: CL
authors.lastname: Parish
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia;
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
authors.forename: Richard J L F
authors.initials: RJ
authors.lastname: Lemmers
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia;
authors.forename: Peter E
authors.initials: PE
authors.lastname: Czabotar
authors.affiliation: Biomolecular Interaction Centre and School of Biological Sciences, University of Canterbury, Christchurch, Private Bag 4800, New Zealand; Department of Biochemistry and Molecular Biology, Bio21 Institute, Melbourne, VIC 3010, Australia.
authors.forename: Renwick C J
authors.initials: RC
authors.lastname: Dobson
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia;
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Ritchie
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia;
authors.forename: Graham F
authors.initials: GF
authors.lastname: Kay
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia;
authors.forename: James M
authors.initials: JM
authors.lastname: Murphy
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia; blewitt@wehi.edu.au.
authors.forename: Marnie E
authors.initials: ME
authors.lastname: Blewitt
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D000076246:CCCTC-Binding Factor; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D018392:Genomic Imprinting; D006657:Histones / Q000378:metabolism; D008297:Male; D008745:Methylation; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome / Q000235:genetics
chemical_list: D000076246:CCCTC-Binding Factor; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C000619698:Ctcf protein, mouse; D006657:Histones; D012097:Repressor Proteins; C529024:SmcHD1 protein, mouse
keywords: Ctcf; Smchd1; clustered protocadherins; epigenetic control