Titre : | CTCF and A-type lamins couple insulation and perinuclear localization of the D4Z4 subtelomeric element in FSHD (P 442) |
Auteurs : | Colloque jeunes chercheurs (7 mars 2008; EVRY - Centre conférence Génocentre Evry) ; Ottaviani A ; Rival-Gervier S ; Boussouar A ; Forster A ; Rondier D ; Bauwens S ; Gilson E ; Magdinier F |
Type de document : | Article |
Année de publication : | 2008 |
Pages : | p. 5 |
Langues: | Anglais |
Résumé : | Both genetic and epigenetic alterations contribute to the Facio-Scapulo-Humeral Dystrophy (FSHD) linked to the reduction of a number of D4Z4 repeated elements at the 4q35 locus. The consequence of this rearrangement remains enigmatic but deletion of these repeats to a threshold of 11 copies might epigenetically dysregulate the FSHD gene(s) in patients through position effect variegation (PEV) and our goal was to test the function of D4Z4 on the regulation of gene silencing. We generated several constructs where different parts or different numbers of D4Z4 were cloned downstream of a reporter gene and followed the expression of the gene over an extended time in culture. We showed that D4Z4 is a bona fide insulator element protecting from PEV and able to block enhancer-promoter communication. The multivalent CTCF protein and A-type Lamins bind to D4Z4 and participate in this insulation activity. Unlike other human telomeres, the 4q35 locus is localized at the periphery of the nucleus and might interact with components of the lamina. We showed that D4Z4 displaces a telomere toward the nuclear periphery in the presence of CTCF and Lamins A/C suggesting that both factors coordinate the long-range chromatin organization of D4Z4 and the tethering of a locus to a specialized nuclear compartment. We further demonstrate that insulation and perinuclear activities of D4Z4 are lost upon multimerization of the repeat, suggesting that the D4Z4 array at the 4q35 locus acts as a CTCF-dependent insulator in FSHD patients but not in normal individuals and might impact on the expression of the genes causing FSHD through the alteration of the 4q35 locus microenvironment. |