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Specific genomic features underlie the co-option of SVA transposons as cis-regulatory elements in the human genome

ABSTRACT: Specific genomic features underlie the co-option of SVA transposons as cis-regulatory elements in the human genome

PROVIDER: PRJNA793877 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17413564_1.fastq.gz	Fastqsanger.gz
	SRR17413564_2.fastq.gz	Fastqsanger.gz
	SRR17413565_1.fastq.gz	Fastqsanger.gz
	SRR17413565_2.fastq.gz	Fastqsanger.gz
	SRR17413566_1.fastq.gz	Fastqsanger.gz

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Specific genomic features underlie the co-option of SVA transposons as cis-regulatory elements in the human genome

Project description:Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, why some TEs are co-opted as functional enhancers while others are not is underappreciated. SINE-Vntr-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-exclusive. Many studies indicated that the SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such process have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication into human stem-cell gene regulation. We found that ~750 SVAs are co-opted as functional cis-regulatory elements in human induced Pluripotent Stem Cells. Co-opted SVAs are significantly closer to genes and harbor more transcription factor binding sites than the not co-opted ones. We show that a long DNA-motif composed of flanking YY1/2 and OCT4 binding sites is enriched in the co-opted SVAs, and that these two factors bind, as predicted, near each other on the TE sequence. Repression of all the ~750 co-opted SVAs by CRISPRi in a line with stem-like properties (NCCIT) led to loss of YY1/OCT4 binding and alteration of neighboring gene expression. Ultimately, SVA repression resulted in ~3,000 differentially expressed genes, 131 of which were the nearest gene to an annotated SVA. In summary, we demonstrated that SVAs contribute significantly to human gene regulation, and that both genomic location and sequence composition contribute to SVA domestication in the gene regulatory networks.

2022-01-04 | GSE192951 | GEO

Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells.

Project description:Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-specific. Many studies indicate that SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such processes have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication into human stem-cell gene regulation. We found that ~750 SVAs are co-opted as functional cis-regulatory elements in human induced pluripotent stem cells. These SVAs are significantly closer to genes and harbor more transcription factor binding sites than non-co-opted SVAs. We show that a long DNA motif composed of flanking YY1/2 and OCT4 binding sites is enriched in the co-opted SVAs and that these two transcription factors bind consecutively on the TE sequence. We used CRISPRi to epigenetically repress active SVAs in stem cell-like NCCIT cells. Epigenetic perturbation of active SVAs strongly attenuated YY1/OCT4 binding and influenced neighboring gene expression. Ultimately, SVA repression resulted in ~3,000 differentially expressed genes, 131 of which were the nearest gene to an annotated SVA. In summary, we demonstrated that SVAs modulate human gene expression, and uncovered that location and sequence composition contribute to SVA domestication into gene regulatory networks.

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Mini-heterochromatin domains constrain the cis-regulatory impact of SVA transposons in human brain development and disease

Project description:SVA retrotransposons remain active in humans and contribute to individual genetic variation. Polymorphic SVA alleles harbor gene-regulatory potential and can cause genetic disease. However, how SVA insertions are controlled and functionally impact human disease is unknown. Here, we dissect the epigenetic regulation and influence of SVAs in cellular models of X-linked dystonia-parkinsonism (XDP), a neurodegenerative disorder caused by an SVA insertion at the TAF1 locus. We demonstrate that the KRAB zinc finger protein ZNF91 establishes H3K9me3 and DNA methylation over SVAs, including polymorphic alleles, in human neural progenitor cells. The resulting mini-heterochromatin domains attenuate the cis-regulatory impact of SVAs. This is critical for XDP pathology; removal of local heterochromatin severely aggravates the XDP molecular phenotype, resulting in increased TAF1 intron retention and reduced expression. Our results provide unique mechanistic insights into how human polymorphic transposon insertions are recognized, and their regulatory impact constrained by an innate epigenetic defense system.

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Mini-heterochromatin domains constrain the cis-regulatory impact of SVA transposons in human brain development and disease

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2023-05-18 | GSE231770 | GEO

G-quadruplexes within the SVA retrotransposon modulate TAF1 gene expression in X-linked Dystonia Parkinsonism [RNA-Seq]

Project description:X-linked dystonia parkinsonism (XDP) is an inherited neurodegenerative disease characterized by the antisense insertion of an SVA retrotransposon into the TAF1 gene, encoding for the largest subunit of the basal transcription factor TFIID, which is essential for RNA polymerase II activity. This SVA insertion has been associated with altered TAF1 expression levels, but the cause of this outcome and its link to the development of XDP remain unknown. Unique to the XDP SVA compared to other SVA retrotransposons in the human genome is the amplification of the (GGGAGA)n repeat domain, creating a unique G4-prone region, whose length correlates with age at onset and disease severity. By ChIP-seq and ChIP-qPCR with the anti-G4 antibody BG4, we assessed that G4s are present in the folded state in the XDP SVA of these cells. Using available G4 ligands, we demonstrated that stabilization of the XDP SVA G4s reduces TAF1 transcripts in the exons around and downstream of the SVA, while increasing the transcription of the upstream exons, possibly through a positive feedback loop.

2024-09-04 | GSE250293 | GEO

Single cell transcriptomics profiling of vessel co-option

Project description:Vessel co-option is an alternative mode of tumor vascularization, which contributes to resistance to anti-angiogenic therapy (AAT). In contrast to vessel sprouting (angiogenesis), knowledge about the mechanisms underlying vessel co-option is minimal, precluding therapeutic strategies. We therefore single-cell RNA-sequenced 31,964 cells from a murine lung metastasis model with vessel co-option, characterized by resistance to AAT. Unexpectedly, co-opted endothelial cells (ECs) were transcriptomically indistinguishable from healthy ECs and lacked an activation signature, while co-opted pericytes expressed a quiescence signature, in contrast to activated pericytes during angiogenesis. Compared with cancer cells during angiogenesis, co-opting cancer cells were phenotypically more diverse and enriched in invasive subpopulations. Together, these data reveal new insight into vessel co-option, with possible implications for the development of therapeutic targets.

2021-06-15 | E-MTAB-9227 | biostudies-arrayexpress

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