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Endogenous retrovirus LTR12C hold potential locus-dependent activities as promoter and/or enhancer [RNA-seq]

ABSTRACT: Long terminal repeats (LTRs), which comprise promoter and enhancer region of intact endogenous retroviruses (ERVs), are known to be co-opted for fine-tuning host-coding gene expression as cis-regulatory elements. Since LTRs are mainly silenced by the deposition of repressive epigenetic marks, a substantial activation of LTRs have been found in human cells after treatment with epigenetic inhibitors. Although LTR12C family had highest relative abundance of transcripts among the de-repressed ERV families, functional consequences of the activated LTR12C for host-coding genes remain uncover due to genome-wide alteration of epigenetic landscape resulting in broad transcriptional changes after the epigenetic inhibitor treatments. Here, we transactivated more than 600 LTR12C elements by using single guide RNA-based dCas9-Suntag-VP64, which is a kind of the site-specific targeting technology CRISPR activation system, with minimal off-target events. Interestingly, most of transactivated LTR12C elements acquired H3K27ac-marked enhancer feature, while 20% of them along with enrichment of H3K4me3-marked promoter feature. The enrichment of H3K4me3 signal was likely brought about by downstream regions of LTR12C, such as internal regions of intact ERV9 or other type of retrotransposons.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243546 | GEO | 2024/08/16

REPOSITORIES: GEO

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Project description:Epigenetic priming factors establish a permissive epigenetic landscape which is not required until a later developmental or physiological time point, temporally uncoupling the presence of these factors with their phenotypic effects. One classic example of epigenetic priming is in the context of bivalent chromatin, found in pluripotent stem cells and early embryos at key developmental gene promoters marked by both activating-associated H3K4me3 and repressive-associated H3K27me3 histone modifications. It is currently unknown how these bivalent domains are targeted, or precisely how they impact on lineage commitment. Here we show that the small heterodimerising non-enzymatic DNA binding proteins Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) act as epigenetic priming factors to establish bivalency at a subset of developmental genes. Dppa2/4 localise to the +1 nucleosome position of bivalent genes and while they are not required for pluripotency in embryonic stem cells (ESCs), double knockout cells fail to exit pluripotency and to differentiate efficiently, with delays in upregulating bivalently marked lineage genes. Proteomics reveal that Dppa2/4 interact on chromatin with members of the COMPASS and Polycomb complexes important for H3K4me3 and H3K27me3 deposition, respectively. Epigenetic profiling reveals a striking loss of H3K4me3, H3K27me3, and their associated enzymatic machinery at a significant subset of bivalent promoters in Dppa2/4 mutants, in addition to loss of H2A.Z and chromatin accessibility. In wild-type ESCs, these “Dppa2/4-dependent” bivalent promoters are characterised by low H3K4me3 enrichment and breadth, near-absent expression levels and initiating but not elongating RNA polymerase. Notably, Dppa2/4-dependent promoters are less evolutionarily conserved suggesting that they lack additional safeguard measures to maintain bivalency at these genes in the absence of Dppa2/4. Concomitantly with the loss of bivalency, Dppa2/4-dependent bivalent promoters gain DNA methylation and consequently are no longer able to be effectively activated upon ESC differentiation, leading to defects in cell fate acquisition. Our findings reveal a targeting principle for bivalency to developmental gene promoters poising them for future lineage specific gene activation.

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Endogenous retrovirus LTR12C hold potential locus-dependent activities as promoter and/or enhancer [RNA-seq]

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