Satellite DNAs in Health and Disease.

Tandemly repeated satellite DNAs are major components of centromeres and pericentromeric heterochromatin which are crucial chromosomal elements responsible for accurate chromosome segregation. Satellite DNAs also contribute to genome evolution and the speciation process and are important for the maintenance of the entire genome inside the nucleus. In addition, there is increasing evidence for active and tightly regulated transcription of satellite DNAs and for the role of their transcripts in diverse processes. In this review, we focus on recent discoveries related to the regulation of satellite DNA expression and the role of their transcripts, either in heterochromatin establishment and centromere function or in gene expression regulation under various biological contexts. We discuss the role of satellite transcripts in the stress response and environmental adaptation as well as consequences of the dysregulation of satellite DNA expression in cancer and their potential use as cancer biomarkers.

Alpha Satellite RNA Levels Are Upregulated in the Blood of Patients with Metastatic Castration-Resistant Prostate Cancer.

The aberrant overexpression of alpha satellite DNA is characteristic of many human cancers including prostate cancer; however, it is not known whether the change in the alpha satellite RNA amount occurs in the peripheral tissues of cancer patients, such as blood. Here, we analyse the level of intracellular alpha satellite RNA in the whole blood of cancer prostate patients at different stages of disease and compare it with the levels found in healthy controls. Our results reveal a significantly increased level of intracellular alpha satellite RNA in the blood of metastatic cancers patients, particularly those with metastatic castration-resistant prostate cancer relative to controls. In the blood of patients with localised tumour, no significant change relative to the controls was detected. Our results show a link between prostate cancer pathogenesis and blood intracellular alpha satellite RNA levels. We discuss the possible mechanism which could lead to the increased level of blood intracellular alpha satellite RNA at a specific metastatic stage of prostate cancer. Additionally, we analyse the clinically accepted prostate cancer biomarker PSA in all samples and discuss the possibility that alpha satellite RNA can serve as a novel prostate cancer diagnostic blood biomarker.

Satellite DNA-Mediated Gene Expression Regulation: Physiological and Evolutionary Implication.

Satellite DNAs are tandemly repeated sequences organized in large clusters within (peri)centromeric and/or subtelomeric heterochromatin. However, in many species, satellite DNAs are not restricted to heterochromatin but are also dispersed as short arrays within euchromatin. Such genomic organization together with transcriptional activity seems to be a prerequisite for the gene-modulatory effect of satellite DNAs which was first demonstrated in the beetle Tribolium castaneum upon heat stress. Namely, enrichment of a silent histone mark at euchromatic repeats of a major beetle satellite DNA results in epigenetic silencing of neighboring genes. In addition, human satellite III transcripts induced by heat shock contribute to genome-wide gene silencing, providing protection against stress-induced cell death. Gene silencing mediated by satellite RNA was also shown to be fundamental for the early embryonic development of the mosquito Aedes aegypti. Apart from a physiological role during embryogenesis and heat stress response, activation of satellite DNAs in terms of transcription and proliferation can have an evolutionary impact. Spreading of satellite repeats throughout euchromatin promotes the variation of epigenetic landscapes and gene expression diversity, contributing to the evolution of gene regulatory networks and to genome adaptation in fluctuating environmental conditions.

Heat Stress Affects H3K9me3 Level at Human Alpha Satellite DNA Repeats.

Satellite DNAs are tandemly repeated sequences preferentially assembled into large arrays within constitutive heterochromatin and their transcription is often activated by stress conditions, particularly by heat stress. Bioinformatic analyses of sequenced genomes however reveal single repeats or short arrays of satellite DNAs dispersed in the vicinity of genes within euchromatin. Here, we analyze transcription of a major human alpha satellite DNA upon heat stress and follow the dynamics of "silent" H3K9me3 and "active" H3K4me2/3 histone marks at dispersed euchromatic and tandemly arranged heterochromatic alpha repeats. The results show H3K9me3 enrichment at alpha repeats upon heat stress, which correlates with the dynamics of alpha satellite DNA transcription activation, while no change in H3K4me2/3 level is detected. Spreading of H3K9me3 up to 1-2 kb from the insertion sites of the euchromatic alpha repeats is detected, revealing the alpha repeats as modulators of local chromatin structure. In addition, expression of genes containing alpha repeats within introns as well as of genes closest to the intergenic alpha repeats is downregulated upon heat stress. Further studies are necessary to reveal the possible contribution of H3K9me3 enriched alpha repeats, in particular those located within introns, to the silencing of their associated genes.

Distinct Regulation of the Expression of Satellite DNAs in the Beetle Tribolium castaneum.

In the flour beetle, Tribolium castaneum (peri)centromeric heterochromatin is mainly composed of a major satellite DNA TCAST1 interspersed with minor satellites. With the exception of heterochromatin, clustered satellite repeats are found dispersed within euchromatin. In order to uncover a possible satellite DNA function within the beetle genome, we analysed the expression of the major TCAST1 and a minor TCAST2 satellite during the development and upon heat stress. The results reveal that TCAST1 transcription was strongly induced at specific embryonic stages and upon heat stress, while TCAST2 transcription is stable during both processes. TCAST1 transcripts are processed preferentially into piRNAs during embryogenesis and into siRNAs during later development, contrary to TCAST2 transcripts, which are processed exclusively into piRNAs. In addition, increased TCAST1 expression upon heat stress is accompanied by the enrichment of the silent histone mark H3K9me3 on the major satellite, while the H3K9me3 level at TCAST2 remains unchanged. The transcription of the two satellites is proposed to be affected by the chromatin state: heterochromatin and euchromatin, which are assumed to be the prevalent sources of TCAST1 and TCAST2 transcripts, respectively. In addition, distinct regulation of the expression might be related to diverse roles that major and minor satellite RNAs play during the development and stress response.

Dispersion Profiles and Gene Associations of Repetitive DNAs in the Euchromatin of the Beetle Tribolium castaneum.

Satellite DNAs are tandemly repeated sequences clustered within heterochromatin. However, in some cases, such as the major TCAST1 satellite DNA from the beetle Tribolium castaneum, they are found partially dispersed within euchromatin. Such organization together with transcriptional activity enables TCAST1 to modulate the activity of neighboring genes. In order to explore if other T. castaneum repetitive families have features that could provide them with a possible gene-modulatory role, we compare here the structure, organization, dispersion profiles, and transcription activity of 10 distinct TCAST repetitive families including TCAST1. The genome organization of TCAST families exhibit either satellite-like or transposon-like characteristics. In addition to heterochromatin localization, bioinformatic searches of the assembled genome have revealed dispersion of all families within euchromatin, preferentially in the form of single repeats. Dispersed TCAST repeats are mutually correlated in distribution and are grouped in distinct regions of euchromatin. The repeats are associated with genes, are enriched in introns relative to intergenic regions, and very rarely overlap exons. In spite of the different mechanisms of repeat proliferation, such as transposition and homologous recombination, all TCAST families share a similar frequency of spreading as well as dispersion and gene association profiles. Additionally, TCAST families are transcribed and their transcription is significantly activated by heat stress. A possibility that such common features of TCAST families might be related to their potential gene-modulatory role is discussed.