EpiGenie ran recently ran a review of the new text Epigenetics: A Reference Manual. Now, to present a little taste of what the book has to offer, here’s a summary of one of the chapters.
By Brian P. Chadwick
The sequence of the human genome does not differ considerably from that of other species. The source of variability are DNA repeat elements, termed “junk DNA” in former times, but gaining more and more importance in gene regulation and disease. About half of the genome is comprised of DNA repetitive elements, satellite DNA being one type of repetitive DNA. Satellite DNA is categorized in four groups: The alpha satellite (building up the centromer), microsatellites (units of about 6 nucleotides spanning about 100 base pairs), minisatellites (e.g. telomeres; units of 6-100 nucleotides spanning several kilobases) and macrosatellites (units of about 3000 nucleotides spanning several hundred kilobases).
Three macrosatellites have been described in detail so far: RS447, DXZ4 and D4Z4. The latter two are subject of this book chapter. Both, DXZ4 and D4Z4 represent the largest CpG islands in the human genome.
The X-chromosomal DXZ4 most probably plays an important role in the establishment and maintenance of X chromosome inactivation, a process in which one X chromosome in the female becomes packed in facultative heterochromatin for the sake of gene dosage compensation, and is folded in a special manner (visible as the so-called Barr body in the nuclear periphery during interphase). Stunningly, DXZ4 is euchromatic on the inactive X (Xi) and heterochromatic on the active X (Xa). Depending on the chromatin state, transcribed sense and antisense DXZ4 RNAs differ in length, which could contribute to the maintenance of X inactivation and genomic stability. Furthermore, the euchromatic DXZ4 is bound by the insulator protein CTCF, which may control and maintain the characteristic folding of the Xi.
The autosomal macrosatellite D4Z4 is being investigated in detail due to its strong correlation with one of the most common inherited muscular dystrophies, FSHD (Facioscapulohumoral muscular dystrophy). FSHD is an autosomal dominant disease marked by progressive muscle atrophy of the face, shoulders and upper arms. Almost all individuals with fewer than 11 tandem repeats of D4Z4 on chromosome 4 develop this disease. Besides chromosome 4, D4Z4 arrays can be found on chromosome 10 and Y, but these arrays do not contribute to FSHD. By now, no consistent explanation about how truncated D4Z4 leads to FSHD is available. Unlike the X chromosomal DXZ4, D4Z4 contains a protein coding sequence for DUX4 (double homeobox). The hypothesis that the heterochromatin formed on D4Z4 spreads over and silences upstream genes under healthy conditions, and does not when there are less than 11 repeats, is challenged by the findings that (i) only a certain haplotype is susceptible to FSHD, (ii) complete loss of the array does not induce the disease, and (iii) that a phenotypic FSHD clinically indistinguishable from the classical form, but without truncated D4Z4, exists. Most possibly, a certain epigenetic signature, being common to both the classical and phenotypic FSHD, results in CTCF binding and DNA looping, thereby activating DUX4 and/or DUX4c, both of which having been associated with disturbed myogenesis.
Conclusively, macrosatellites are far from being useless junk DNA. The examples discussed in this book chapter highlight the importance of macrosatellites in the spatial organization of the genome and the control of gene expression.
This chapter summary was provided courtesy of Regina Brunauer who is currently a joint postdoc in the Lunyak and Kennedy labs at the Buck Institute for Age Research.
You can get yourself a copy of Epigenetics: A Reference Manual at the Horizon Press website.