An Evaluation of a SVA Retrotransposon in the FUS Promoter as a Transcriptional Regulator and Its Association to ALS

Abstract

Genetic mutations of FUS have been linked to many diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration. A primate specific and polymorphic retrotransposon of the SINE-VNTR-Alu (SVA) family is present upstream of the FUS gene. Here we have demonstrated that this retrotransposon can act as a classical transcriptional regulatory domain in the context of a reporter gene construct both in vitro in the human SK-N-AS neuroblastoma cell line and in vivo in a chick embryo model. We have also demonstrated that the SVA is composed of multiple distinct regulatory domains, one of which is a variable number tandem repeat (VNTR). The ability of the SVA and its component parts to direct reporter gene expression supported a hypothesis that this region could direct differential FUS expression in vivo. The SVA may therefore contribute to the modulation of FUS expression exhibited in and associated with neurological disorders including ALS where FUS regulation may be an important parameter in progression of the disease. As VNTRs are often clinical associates for disease progression we determined the extent of polymorphism within the SVA. In total 2 variants of the SVA were identified based within a central VNTR. Preliminary analysis addressed the association of these SVA variants within a small sporadic ALS cohort but did not reach statistical significance, although we did not include other parameters such as SNPs within the SVA or an environmental factor in this analysis. The latter may be particularly important as the transcriptional and epigenetic properties of the SVA are likely to be directed by the environment of the cell.

Lineage specific evolution of the VNTR composite retrotransposon central domain and its role in retrotransposition of gibbon LAVA elements

“…Our finding that remodelling of VNTRs takes place at the DNA level is in line with a recent report on the existence of allelic variants of SVA VNTRs [ 10 , 28 ]. Interestingly, the authors of the studies found RU copy number variation only in the 3’ part characterized by the long F and K repeat units (VNTR according to their nomenclature) and not in the 5’ part (TR according to their nomenclature) which comprises 37 to 40 bp RUs (A, B and C) only.…”

Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1

“…At least 85 human diseases are currently linked to active retroelements, with at least 12 associated specifically with SVAs ( 28 , 34 – 45 ). These SVA insertions have been associated with various types of transcriptional interference, which may be due to their capacities to activate cryptic splice sites, generate transcripts via intrinsic promoter activity, and form G-quadruplex (G4) structures that inhibit the progression of RNA polymerase II (RNAP II) ( 32 , 46 – 54 ). The functional consequences of the XDP-specific SVA are not yet known.…”

Potential impact of primate-specific SVA retrotransposons during the evolution of human cognitive function

“…6 SVA elements represent the youngest non-LTR retrotransposon family in humans and the human genome harbors approximately 2700 SVAs. [7][8][9] We and others have demonstrated that SVA elements have properties of transcriptional regulators of gene expression both in vivo and in vitro, 8,10,11 and that a significant number of SVA elements are located within 10kb of the major transcriptional start site of many genes. 8 Therefore, SVA insertions established in the hominoid lineage could be responsible for altering the transcriptome in a developmental, tissue-specific or stimulus inducible manner, as was already suggested earlier for Alu elements and demonstrated for LTR sequences of endogenous retroviruses.…”