Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 33, Pages 12463-12468Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0605343103
Keywords
chromatin domain; chromosome conformation capture; transcription; fragile X locus
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Funding
- NHGRI NIH HHS [HG003143, R01 HG003143] Funding Source: Medline
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We have analyzed the effects of gene activation on chromatin conformation throughout an approximate to 170-kb region comprising the human fragile X locus, which includes a single expressed gene, FMR1 (fragile X mental retardation 1). We have applied three approaches: (t) chromosome conformation capture, which assesses relative interaction frequencies of chromatin segments; (h) an extension of this approach that identifies domains whose conformation differs from the average, which we developed and named chromosome conformation profiling; and (M) ChIP analysis of histone modifications. We find that, in normal cells where FMR1 is active, the FMR1 promoter is at the center of a large (-50 kb) domain of reduced intersegment interactions. In contrast, in fragile X cells where FMR1 is inactive, chromatin conformation is uniform across the entire region. We also find that histone modifications that are characteristic of active genes occur tightly localized around the FMR1 promoter in normal cells and are absent in fragile X cells. Therefore, the expression-correlated change in conformation affects a significantly larger domain than that marked by histone modifications. Domain-wide changes in interaction probability could reflect increased chromatin expansion and may also be related to an altered spatial disposition that results in increased intermingling with unrelated loci. The described approaches are widely applicable to the study of conformational changes of any locus of interest.
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