Article

CTCF, cohesin, and histone variants: connecting the genome.

Department of Biology, Faculty of Sciences, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada.
Biochemistry and Cell Biology (Impact Factor: 2.92). 10/2011; 89(5):505-13. DOI: 10.1139/o11-052
Source: PubMed

ABSTRACT During the last decades our view of the genome organization has changed. We moved from a linear view to a looped view of the genome. It is now well established that inter- and intra-connections occur between chromosomes and play a major role in gene regulations. These interconnections are mainly orchestrated by the CTCF protein, which is also known as the "master weaver" of the genome. Recent advances in sequencing and genome-wide studies revealed that CTCF binds to DNA at thousands of sites within the human genome, providing the possibility to form thousands of genomic connection hubs. Strikingly, two histone variants, namely H2A.Z and H3.3, strongly co-localize at CTCF binding sites. In this article, we will review the recent advances in CTCF biology and discuss the role of histone variants H2A.Z and H3.3 at CTCF binding sites.

0 Bookmarks
 · 
89 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Centromeres are essential for ensuring proper chromosome segregation in eukaryotes. Their definition relies on the presence of a centromere-specific H3 histone variant CenH3, known as CENP-A in mammals. Its overexpression in aggressive cancers raises questions concerning its effect on chromatin dynamics and contribution to tumorigenesis. We find that CenH3 overexpression in human cells leads to ectopic enrichment at sites of active histone turnover involving a heterotypic tetramer containing CenH3-H4 with H3.3-H4. Ectopic localization of this particle depends on the H3.3 chaperone DAXX rather than the dedicated CenH3 chaperone HJURP. This aberrant nucleosome occludes CTCF binding and has a minor effect on gene expression. Cells overexpressing CenH3 are more tolerant of DNA damage. Both the survival advantage and CTCF occlusion in these cells are dependent on DAXX. Our findings illustrate how changes in histone variant levels can disrupt chromatin dynamics and suggests a possible mechanism for cell resistance to anticancer treatments.
    Molecular cell 02/2014; · 14.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The genetic interrogation and reprogramming of cells requires methods for robust and precise targeting of genes for expression or repression. The CRISPR-associated catalytically inactive dCas9 protein offers a general platform for RNA-guided DNA targeting. Here, we show that fusion of dCas9 to effector domains with distinct regulatory functions enables stable and efficient transcriptional repression or activation in human and yeast cells, with the site of delivery determined solely by a coexpressed short guide (sg)RNA. Coupling of dCas9 to a transcriptional repressor domain can robustly silence expression of multiple endogenous genes. RNA-seq analysis indicates that CRISPR interference (CRISPRi)-mediated transcriptional repression is highly specific. Our results establish that the CRISPR system can be used as a modular and flexible DNA-binding platform for the recruitment of proteins to a target DNA sequence, revealing the potential of CRISPRi as a general tool for the precise regulation of gene expression in eukaryotic cells.
    Cell 07/2013; · 31.96 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Heterochromatin displays repressive histone marks that down-regulate transcription. In the absence of specialized barriers, these repressive marks spread onto nearby nucleosomes and induce transcriptional silencing of these regions. Accordingly, in various species, transgenes that are experimentally inserted directly next to telomeric repeats are silenced. Transcriptional repression induced by the spreading of telomeric heterochromatin is known as the "telomere position effect". Although it is attenuated by the presence of natural subtelomeric barriers acting against the spreading of telomeric heterochromatin, telomere-induced silencing is also observed at the level of endogenous loci where it was initially proposed to provide a mean to regulate gene expression during senescence. This, however, remains to be formally demonstrated. Here, I review the current evidences for a telomere position effect, from yeast to human.
    Medecine sciences: M/S 02/2014; 30(2):173-8. · 0.56 Impact Factor

Full-text

View
5 Downloads
Available from
Jun 23, 2014