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Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):E3535-44. doi: 10.1073/pnas.1504232112. Epub 2015 Jun 19.

Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation.

Author information

1
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia;
2
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;
3
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia;
4
Biomolecular Interaction Centre and School of Biological Sciences, University of Canterbury, Christchurch, Private Bag 4800, New Zealand;
5
The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC 3010, Australia;
6
Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
7
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.
8
Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia;
9
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; University of Melbourne, Melbourne, VIC 3010, Australia; blewitt@wehi.edu.au.

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.

KEYWORDS:

Ctcf; Smchd1; clustered protocadherins; epigenetic control

PMID:
26091879
PMCID:
PMC4500281
DOI:
10.1073/pnas.1504232112
[Indexed for MEDLINE]
Free PMC Article

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