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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192951 | GEO | 2022/01/04

REPOSITORIES: GEO

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Genetic deletion of ZNF91 in human embryonic stem cells leads to ectopic activation of SVAs and collective upregulation of KRAB zinc finger gene clusters

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2021-01-28 | GSE162571 | GEO

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

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2023-11-01 | GSE245093 | GEO

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Chromatin profiling of the innate immune response in bovine MDBK cells

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Amplicon-seq of SVA methylation in human sperm

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2021-08-01 | GSE174562 | GEO

Hominid-specific transposable elements and KRAB-ZFPs facilitate human embryonic genome activation and transcription in naïve hESCs [ATAC-seq]

Project description:Transposable elements (TEs) are key to the evolutionary turnover of regulatory sequences. How they can play such an essential role in spite of their genotoxic potential is unknown. Here, we demonstrate that KRABcontaining zinc finger proteins control the timely and pleiotropic engagement of TE-derived cis-regulators of transcription. We first observed that evolutionary recent TEs of the SVA, HERVK and HERVH subgroups are major contributors to chromatin opening during human embryonic genome activation and act as KLF-stimulated enhancers in naïve embryonic stem cells. We then found that KZFPs of corresponding evolutionary ages are simultaneously induced and repress the transcriptional activity of these TEs. We finally determined that the same KZFP-controlled TE-based enhancers later serve as developmental and tissue-specific regulators of gene expression. Thus, by taming the transcriptional impact of TEs during early embryogenesis, KZFPs allow for their genome-wide incorporation into transcriptional networks, thereby contributing to the species-specificity of human genome regulation.

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Hominid-specific transposable elements and KRAB-ZFPs facilitate human embryonic genome activation and transcription in naïve hESCs [ChIP-seq]

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