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Project description:BackgroundTransposable elements (TEs) have colonized the genomes of most metazoans, and many TE-embedded sequences function as cis-regulatory elements (CREs) for genes involved in a wide range of biological processes from early embryogenesis to innate immune responses. Because of their repetitive nature, TEs have the potential to form CRE platforms enabling the coordinated and genome-wide regulation of protein-coding genes by only a handful of trans-acting transcription factors (TFs).ResultsHere, we directly test this hypothesis through mathematical modeling and demonstrate that differences in expression at protein-coding genes alone are sufficient to estimate the magnitude and significance of TE-contributed cis-regulatory activities, even in contexts where TE-derived transcription fails to do so. We leverage hundreds of overexpression experiments and estimate that, overall, gene expression is influenced by TE-embedded CREs situated within approximately 500 kb of promoters. Focusing on the cis-regulatory potential of TEs within the gene regulatory network of human embryonic stem cells, we find that pluripotency-specific and evolutionarily young TE subfamilies can be reactivated by TFs involved in post-implantation embryogenesis. Finally, we show that TE subfamilies can be split into truly regulatorily active versus inactive fractions based on additional information such as matched epigenomic data, observing that TF binding may better predict TE cis-regulatory activity than differences in histone marks.ConclusionOur results suggest that TE-embedded CREs contribute to gene regulation during and beyond gastrulation. On a methodological level, we provide a statistical tool that infers TE-dependent cis-regulation from RNA-seq data alone, thus facilitating the study of TEs in the next-generation sequencing era.
| S-EPMC10637000 | biostudies-literature
Project description:Statistical learning quantifies transposable element-mediated cis-regulation
| PRJNA859814 | ENA
Project description:Mouse ESCs and EpiSCs represent naive and primed states of plurioptency corresponding to two consecutive stages of embryo development. Here we map their chromatin accessibility landscapes and show that naive specific open chromatin are enriched with motifs for Oct/Sox/Klf/TCF and primed one with AP1 motifs. The AP1 founding member c-Jun is expressed in EpiSCs and occupies both open and closed chromatin. Yet, c-Jun deficiency has no impact on the self renewal nor the transcription program of EpiSCs. However, in a Klf4-driven reprogramming system, we show that c-Jun-/- EpiSCs undergo primed to naive transition more efficiently than wild type cells and Klf4 evicts c-JUN from wild type chromatin. These results suggest that c-Jun is a pioneer factor not to regulate transcription but to prevent backward reprogramming during naive-primed transition, thus providing a molecular basis for the forward principle in development.
2020-12-31 | GSE127925 | GEO
Project description:Mouse ESCs and EpiSCs represent naive and primed states of plurioptency corresponding to two consecutive stages of embryo development. Here we map their chromatin accessibility landscapes and show that naive specific open chromatin are enriched with motifs for Oct/Sox/Klf/TCF and primed one with AP1 motifs. The AP1 founding member c-Jun is expressed in EpiSCs and occupies both open and closed chromatin. Yet, c-Jun deficiency has no impact on the self renewal nor the transcription program of EpiSCs. However, in a Klf4-driven reprogramming system, we show that c- Jun-/- EpiSCs undergo primed to naive transition more efficiently than wild type cells and Klf4 evicts c-JUN from wild type chromatin. These results suggest that c-Jun is a pioneer factor not to regulate transcription but to prevent backward reprogramming during naive-primed transition, thus providing a molecular basis for the forward principle in development.
2020-12-31 | GSE127921 | GEO
Project description:Mouse ESCs and EpiSCs represent naive and primed states of plurioptency corresponding to two consecutive stages of embryo development. Here we map their chromatin accessibility landscapes and show that naive specific open chromatin are enriched with motifs for Oct/Sox/Klf/TCF and primed one with AP1 motifs. The AP1 founding member c-Jun is expressed in EpiSCs and occupies both open and closed chromatin. Yet, c-Jun deficiency has no impact on the self renewal nor the transcription program of EpiSCs. However, in a Klf4-driven reprogramming system, we show that c- Jun-/- EpiSCs undergo primed to naive transition more efficiently than wild type cells and Klf4 evicts c-JUN from wild type chromatin. These results suggest that c-Jun is a pioneer factor not to regulate transcription but to prevent backward reprogramming during naive-primed transition, thus providing a molecular basis for the forward principle in development.
2020-12-31 | GSE127920 | GEO
Project description:During development, human primordial germ cells (hPGCs) transition through a transcriptional and epigenetic state similar to pre-implantation epiblast cells called naive ground-state pluripotency. Diagnostic transcription factors that define this state include TFAP2C, KLF4, and TFCP2L1, with TFAP2C necessary for both establishment of the naive-like state in hPGC-like cells (hPGCLCs) as well as establishment and self-renewal of naive human embryonic stem cells (hESCs). Here, we show that KLF4 and TFCP2L1 are not required for hPGC specification or establishment of the naive-like state in hPGCLCs. Instead, KLF4 and TFCP2L1 are each required for reversion of primed hESCs to the self-renewing naive ground state. Additionally, TFCP2L1 but not KLF4 function after hPGC specification in the proliferation of the hPGCLC population.
2022-04-30 | GSE148717 | GEO
Project description:Transposable elements (TEs) are hypothesized to play important roles in shaping genome evolution following whole-genome duplications (WGDs), including rewiring of gene regulation. In a recent analysis, duplicate gene copies that had evolved higher expression in liver following the salmonid WGD ∼100 million years ago were associated with higher numbers of predicted TE-derived cis-regulatory elements (TE-CREs). Yet, the ability of these TE-CREs to recruit transcription factors (TFs) in vivo and impact gene expression remains unknown. Here, we evaluated the gene-regulatory functions of 11 TEs using luciferase promoter reporter assays in Atlantic salmon (Salmo salar) primary liver cells. Canonical Tc1-Mariner elements from intronic regions showed no or small repressive effects on transcription. However, other TE-CREs upstream of transcriptional start sites increased expression significantly. Our results question the hypothesis that TEs in the Tc1-Mariner superfamily, which were extremely active following WGD in salmonids, had a major impact on regulatory rewiring of gene duplicates, but highlights the potential of other TEs in post-WGD rewiring of gene regulation in the Atlantic salmon genome.
| S-EPMC10085797 | biostudies-literature
Project description:Human pluripotent stem cells have two major pluripotent states, primed and naive, and the heterogeneity among cell lines in each pluripotent state remains a major unresolved problem. We showed that the overexpression of H1FOO-DD, which has a short expression period by fusing the destabilized domain to the maternal-specific linker histone H1FOO, together with OCT4, SOX2, KLF4 and LMYC in human somatic cells improves the quality of reprogramming to primed and naive pluripotency.
2024-05-01 | GSE253926 | GEO
Project description:Human pluripotent stem cells have two major pluripotent states, primed and naive, and the heterogeneity among cell lines in each pluripotent state remains a major unresolved problem. We showed that the overexpression of H1FOO-DD, which has a short expression period by fusing the destabilized domain to the maternal-specific linker histone H1FOO, together with OCT4, SOX2, KLF4 and LMYC in human somatic cells improves the quality of reprogramming to primed and naive pluripotency.
2024-05-01 | GSE224699 | GEO
Project description:Human pluripotent stem cells have two major pluripotent states, primed and naive, and the heterogeneity among cell lines in each pluripotent state remains a major unresolved problem. We showed that the overexpression of H1FOO-DD, which has a short expression period by fusing the destabilized domain to the maternal-specific linker histone H1FOO, together with OCT4, SOX2, KLF4 and LMYC in human somatic cells improves the quality of reprogramming to primed and naive pluripotency.
2024-05-01 | GSE224698 | GEO