The SST1/NBL2 satellites have been associated with cancer, particularly through epigenetic and transcriptional alterations. They are located mainly on acrocentric chromosomes (with unequal arms) and are a highly valuable model “because they concentrate many of the extreme characteristics of the human repetitive genome: they are large tandemly repeated sequences, with high structural complexity, dynamic epigenetic regulation and the production of non-coding RNAs,” says Sonia V. Forcales, of the Department of Pathology and Experimental Therapeutics at the UB and principal investigator of the Immunity, Inflammation and Cancer research group at IDIBELL.
In cancer, these repetitive regions of the genome are frequently demethylated — the loss of methyl CH₃ groups — one of the most common epigenetic alterations in human tumours. The team contributed to characterizing the epigenetic dysregulation in these macrosatellites and to describing TNBL, a non-coding RNA derived from NBL2 regions frequently hypomethylated in tumours. This transcript can interact with factors involved in splicing, the DNA damage response and nucleolar function.
“This suggests possible connections between the repetitive genome and functional molecular processes in tumour biology. However, we still do not know to what extent SST1/NBL2 are directly involved in these processes or what the exact underlying mechanism is,” notes the researcher from the UB and IDIBELL.
Recent studies have also identified the regions containing SST1/NBL2 as genomic loci involved in Robertsonian translocations, that is, the most common chromosomal rearrangements in humans. When these rearrangements involve chromosome 21, they can give rise to a form of trisomy 21, which accounts for a minority of cases of Down syndrome.
These data do not indicate that SST1/NBL2 is the sole cause, but they do reinforce the idea that these regions may contribute to the structural vulnerability of acrocentric chromosomes. In this context, these macrosatellites are relevant because they are located in acrocentric regions involved in this type of rearrangement, but it cannot be concluded that they are the direct cause of the pathology,” the researcher notes.
Other human diseases have also been linked to families of macrosatellites and repetitive genome sequences. For example, the D4Z4 macrosatellite is involved in facioscapulohumeral muscular dystrophy, and alterations in the methylation of repetitive regions such as SST1/NBL2 and D4Z4 have been described in ICF syndrome, a rare disease associated with immunodeficiency, chromosomal instability and facial anomalies.
A revolution in the study of the human repetitive genome
Current techniques allow researchers to study regions of the genome that are considered irrelevant not because they were, but because the necessary tools to explore their biological complexity did not exist. “The great challenge is no longer to fully sequence the human genome, but to understand the function of the repetitive regions that for decades lay outside the focus of genomics,” says Sonia V. Forcales.
Long-read sequencing technologies — such as Oxford Nanopore and PacBio — and the new telomere-to-telomere (T2T) assemblies of the human genome have revolutionized the ability to reconstruct regions such as SST1/NBL2, which consist of large arrays of similar repeated sequences and had until recently been absent, fragmented or poorly represented in reference genomes produced by more conventional technologies. In parallel, traditional techniques — RNA-FISH, DNA-FISH, RNA pull-down and Northern blot — have been key to studying their nuclear localization, the expression of the RNAs derived from these sequences and their molecular interactions.
This new level of resolution is already transforming the way we can study the human repetitive genome. For example, “it will make it possible to study variability between individuals, between tumours, as well as their epigenetic marks and SST1/NBL2-derived RNAs more reliably,” the authors point out.
In the future, the team aims to characterize possible variants or isoforms of these RNAs, as well as their regulation and epigenetic modifications. The goal is to determine whether these RNAs play a functional role in tumour processes, rather than being merely a consequence of cancer-related epigenetic dysregulation.
“We are still in a basic research phase, but if we confirm that these RNAs functionally contribute to tumour processes, it could open up new avenues to explore their role as biomarkers or therapeutic vulnerabilities,” the researcher concludes.