Genome-wide analysis validates aberrant methylation in fragile X syndrome is specific to the FMR1locus

AbstractShort tandem repeat (STR) instability is causally linked to pathologic transcriptional silencing in a subset of repeat expansion disorders. In fragile X syndrome (FXS), instability of a single CGG STR tract is thought to repress FMR1 via local DNA methylation. Here, we report the acquisition of more than ten Megabase-sized H3K9me3 domains in FXS, including a 5-8 Megabase block around FMR1. Distal H3K9me3 domains encompass synaptic genes with STR instability, and spatially co-localize in trans concurrently with FMR1 CGG expansion and the dissolution of TADs. CRISPR engineering of mutation-length FMR1 CGG to normal-length preserves heterochromatin, whereas cut-out to pre-mutation-length attenuates a subset of H3K9me3 domains. Overexpression of a pre-mutation-length CGG de-represses both FMR1 and distal heterochromatinized genes, indicating that long-range H3K9me3-mediated silencing is exquisitely sensitive to STR length. Together, our data uncover a genome-wide surveillance mechanism by which STR tracts spatially communicate over vast distances to heterochromatinize the pathologically unstable genome in FXS.One-Sentence SummaryHeterochromatinization of distal synaptic genes with repeat instability in fragile X is reversible by overexpression of a pre-mutation length CGG tract.

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Genome-wide analysis of aberrant methylation in human breast cancer cells using methyl-DNA immunoprecipitation combined with high-throughput sequencing

BMC Genomics ◽

10.1186/1471-2164-11-137 ◽

2010 ◽

Vol 11 (1) ◽

pp. 137 ◽

Cited By ~ 129

Author(s):

Yoshinao Ruike ◽

Yukako Imanaka ◽

Fumiaki Sato ◽

Kazuharu Shimizu ◽

Gozoh Tsujimoto

Keyword(s):

Breast Cancer ◽

High Throughput ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

High Throughput Sequencing ◽

Aberrant Methylation ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Genome Wide Analysis ◽

Genome Wide

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Common Variant Associations with Fragile X Syndrome

10.1101/115998 ◽

2017 ◽

Author(s):

James J Crowley ◽

Jin Szatkiewicz ◽

Anna K Kähler ◽

Paola Giusti-Rodriguez ◽

NaEshia Ancalade ◽

...

Keyword(s):

Fragile X Syndrome ◽

Odds Ratio ◽

De Novo ◽

Fragile X ◽

De Novo Mutation ◽

Risk Haplotype ◽

Functional Genomic ◽

Cgg Repeats ◽

Genome Wide ◽

Protective Haplotype

AbstractFragile X syndrome is a common cause of intellectual disability. It is usually caused by a de novo mutation which often occur on multiple haplotypes and should not be detectible using genome-wide association (GWA). We conducted GWA 89 male FXS cases and 266 male controls, and detected multiple genome-wide significant signals near FMR1 (odds ratio=8.10, P=2.5×10−10). These findings withstood robust attempts at falsification. Fine-mapping did not serve to narrow the interval (minimum P=1.13×l0−14), and functional genomic integration (including 5C data we generated for this region) did not provide a mechanistic hypothesis. Controls carrying a risk haplotype had significantly longer and more variable FMR1 CGG repeats than controls with the protective haplotype (P=4.75×10−5) which may predispose toward increases in CGG number to the pre-mutation range over many generations. This is a salutary reminder of the complexity of even “simple” monogenetic disorders.

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