A nuclear matrix attachment site in the 4q35 locus has an enhancer-blocking activity in vivo: Implications for the facio-scapulo-humeral dystrophy

Abstract

Facio-scapulo-humeral dystrophy (FSHD), a muscular hereditary disease with a prevalence of 1 in 20,000, is caused by a partial deletion of a subtelomeric repeat array on chromosome 4q. Earlier, we demonstrated the existence in the vicinity of the D4Z4 repeat of a nuclear matrix attachment site, FR-MAR, efficient in normal human myoblasts and nonmuscular human cells but much weaker in muscle cells from FSHD patients. We now report that the D4Z4 repeat contains an exceptionally strong transcriptional enhancer at its 5′-end. This enhancer up-regulates transcription from the promoter of the neighboring FRG1 gene. However, an enhancer blocking activity was found present in FR-MAR that in vitro could protect transcription from the enhancer activity of the D4Z4 array. In vivo, transcription from the FRG1 and FRG2 genes could be down- or up-regulated depending on whether or not FR-MAR is associated with the nuclear matrix. We propose a model for an etiological role of the delocalization of FR-MAR in the genesis of FSHD.

Facioscapulohumeral muscular dystrophy (FSHD): an enigma unravelled?

“…The FR-MAR was found to be weakened in FSHD muscle cells, thus allowing the D4Z4 array and the 4q35 genes to be contained within a single chromatin loop. This may then permit the D4Z4-associated enhancer to up-regulate transcription of several genes in the vicinity (Petrov et al 2008).…”

D4Z4as a prototype of CTCF and lamins-dependent insulator in human cells

“…A second and non-exclusive model relies on the involvement of fixed nuclear structures in barrier activity demonstrated in budding yeast, where nuclear pore components were identified in a screen for boundary activity, 22 or in higher eukaryotes through the association with the nuclear matrix or the nucleolar surface. 15,[23][24][25] over 100 millions years ago.…”

DNA polymorphism and epigenetic marks modulate the affinity of a scaffold/matrix attachment region to the nuclear matrix

“…10 Moreover, the strength and specificity of S/MAR attachment to the NM varies during ontogenesis, 11 in cancer 12 and various genetic diseases such as facioscapulohumeral dystrophy (FSHD). 13,14 Several factors potentially affect the association of DNA with the NM. These include the DNA sequence itself and its epigenetic state.…”

“…[15][16][17][18] We have recently characterized an S/MAR within the subtelomeric region of chromosome 4q. 13,14 This region ( Figure 1a) has a complex structure and includes the D4Z4 macrosatellite repeat array, which consists of 3.3 kb repeated units with a number of units varying between individuals. 19 This S/MAR, designated as FR-MAR for FSHD-related matrix attachment region, 13 is located centromerically to the D4Z4 array and includes a simple sequence length polymorphism (SSLP) (for a review see Dmitriev et al 20 ).…”

“…Thus, we have shown that in FSHD the FR-MAR is partially detached from the NM. 13,14 The mechanisms underlying the observed interaction between the FR-MAR and the NM remain largely unknown. Several factors could have a role.…”