Emerging roles of macrosatellite repeats in genome organization and disease development

Abstract

Abundant repetitive DNA sequences are an enigmatic part of the human genome. Despite increasing evidence on the functionality of DNA repeats, their biologic role is still elusive and under frequent debate. Macrosatellites are the largest of the tandem DNA repeats, located on one or multiple chromosomes. The contribution of macrosatellites to genome regulation and human health was demonstrated for the D4Z4 macrosatellite repeat array on chromosome 4q35. Reduced copy number of D4Z4 repeats is associated with local euchromatinization and the onset of facioscapulohumeral muscular dystrophy. Although the role other macrosatellite families may play remains rather obscure, their diverse functionalities within the genome are being gradually revealed. In this review, we will outline structural and functional features of coding and noncoding macrosatellite repeats, and highlight recent findings that bring these sequences into the spotlight of genome organization and disease development.

Keywords: DNA repeats; epigenetics; genome organization; macrosatellite repeats; noncoding genome.

Figure 1.

Repetitive DNA in the human genome. The diagram shows various classes of DNA repeats in the human genome, classified according to their pattern of occurrence.

Figure 2.

D4Z4 regulates local chromatin structure and expression of surrounding genes via long noncoding RNA. Healthy individuals carry between 11 and 150 copies of D4Z4 macrosatellite in the subtelomeric regions of chromosome 4 (4q35). D4Z4 repeats are highly methylated and enriched in H3K9me3. D4Z4 repeats are targets of Polycomb group proteins (PcG), with a resulting repressive chromatin structure and surrounding genes in transcriptionally silent state. In patients with facioscapulohumeral dystrophy 1 (FSHD1) there is a reduction of D4Z4 copy number to between 1 and 10 copies. The contracted allele loses heterochromatin features (DNA methylation, H3K9me3, H3K27me3) and expresses a long noncoding RNA DBE-T, from a promoter distal to the repeat array, that binds and recruits Tritorax group protein Ash1L in cis, resulting in H3 lysine 36 dimethylation and long-range gene up regulation. In addition, transcription within each repeat unit was reported to occur bidirectionally, indicated by red (sense transcription) and blue (antisense transcription) arrows. Sense and antisense transcripts originate from promoters mapped upstream and downstream of DUX4 ORF, respectively, and are transcribed through multiple D4Z4 repeat units. Those transcripts are suggested to give rise to small ncRNAs. Model design based on,ref. and .

Figure 3.

DXZ4 plays a role in genome organization and Xi chromosome higher order structure. DXZ4 harbors opposite chromatin structures on Xa and Xi chromosome, which differ from the surrounding chromatin. On Xi, DXZ4 displays features of euchromatin (hypomethylated CpGs and H3K4me2) and is bound by CTCF. Arrays on Xa and Xi chromosome are transcriptionally active; however, on Xa DXZ4 is transcribed in a long sense transcript and four small antisense RNAs, 3 of which overlap H3K9me3 peaks. On Xi chromosome, DXZ4 is transcribed into long sense and antisense transcripts. DXZ4 on Xi chromosome is necessary for regulating Xi higher order structures. Black dots represent methylated CpGs, white dots unmethylated CpGs. Model design based on ref.

Figure 4.

NBL2 macrosatellites are frequently hypomethylated in colorectal cancer (CRC). In normal colon epithelium, NBL2/SST1 repeats display features of constitutive heterochromatin, with high levels of DNA methylation and H3K9me3. In CRC, NBL2/SST1 repeats undergo gradual hypomethylation during aging associated with wild type TP53. Some CRC patients harbor strongly hypomethylated NBL2/SST1 repeats that implicates mechanisms other than aging, and preferentially occurs in mutated TP53 tumors. Hypomethylation of NBL2 results in reprogramming of NBL2 chromatin state from constitutive heterochromatin to facultative heterochromatin characterized by a gain in H3K27me3. NBL2 DNA hypomethylation is linked to increased genomic damage in cases with wild-type TP53. Black dots represent methylated CpGs, white dots unmethylated CpGs. Model design based on ref.