title: Evolutionary genomic remodelling of the human 4q subtelomere (4q35.2).
abstract: BACKGROUND
  In order to obtain insights into the functionality of the human 4q35.2 domain harbouring the facioscapulohumeral muscular dystrophy (FSHD) locus, we investigated in African apes genomic and chromatin organisations, and the nuclear topology of orthologous regions.
  
  
  RESULTS
  A basic block consisting of short D4Z4 arrays (10-15 repeats), 4q35.2 specific sequences, and approximately 35 kb of interspersed repeats from different LINE subfamilies was repeated at least twice in the gorilla 4qter. This genomic organisation has undergone evolutionary remodelling, leading to the single representation of both the D4Z4 array and LINE block in chimpanzee, and the loss of the LINE block in humans. The genomic remodelling has had an impact on 4qter chromatin organisation, but not its interphase nuclear topology. In comparison with humans, African apes show very low or undetectable levels of FRG1 and FRG2 histone 4 acetylation and gene transcription, although histone deacetylase inhibition restores gene transcription to levels comparable with those of human cells, thus indicating that the 4qter region is capable of acquiring a more open chromatin structure. Conversely, as in humans, the 4qter region in African apes has a very peripheral nuclear localisation.
  
  
  CONCLUSIONS
  The 4q subtelomere has undergone substantial genomic changes during evolution that have had an impact on chromatin condensation and the region's transcriptional regulation. Consequently, the 4qter genes in African apes and humans seem to be subjected to a different strategy of regulation in which LINE and D4Z4 sequences may play a pivotal role. However, the effect of peripheral nuclear anchoring of 4qter on these regulation mechanisms is still unclear. The observed differences in the regulation of 4qter gene expression between African apes and humans suggest that the human 4q35.2 locus has acquired a novel functional relevance.
authors.affiliation: Department of Biology and Genetics for Medical Sciences, University of Milan, Milan, Italy. enrico.ginelli@unimi.it
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bodega
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Cardone
authors.forename: Stefan
authors.initials: S
authors.lastname: Müller
authors.forename: Michaela
authors.initials: M
authors.lastname: Neusser
authors.forename: Francesca
authors.initials: F
authors.lastname: Orzan
authors.forename: Elena
authors.initials: E
authors.lastname: Rossi
authors.forename: Elena
authors.initials: E
authors.lastname: Battaglioli
authors.forename: Anna
authors.initials: A
authors.lastname: Marozzi
authors.forename: Paola
authors.initials: P
authors.lastname: Riva
authors.forename: Mariano
authors.initials: M
authors.lastname: Rocchi
authors.forename: Raffaella
authors.initials: R
authors.lastname: Meneveri
authors.forename: Enrico
authors.initials: E
authors.lastname: Ginelli
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D002843:Chromatin / Q000235:genetics; D002894:Chromosomes, Human, Pair 4; D033481:Chromosomes, Mammalian; D003001:Cloning, Molecular; D019143:Evolution, Molecular; D005819:Genetic Markers; D015698:Genomic Library; D006071:Gorilla gorilla / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics*; D002679:Pan troglodytes / Q000235:genetics*; D020161:Physical Chromosome Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002843:Chromatin; D005819:Genetic Markers