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Regulation of endogenous retrovirus-derived regulatory elements by GATA2/3 and MSX2 in human trophoblast stem cells (ChIP-seq)

ABSTRACT: The placenta is an organ with extraordinary phenotypic diversity in eutherian mammals. Recent evidence suggest that numerous human placental enhancers are evolved from lineage-specific insertions of endogenous retroviruses (ERVs), yet the transcription factors (TFs) underlying their regulation remain largely elusive. Here, by first focusing on MER41, a primate-specific ERV family previously linked to placenta and innate immunity, we uncover the binding motifs of multiple crucial trophoblast TFs (GATA2/3, MSX2, GRHL2) in addition to innate immuninty TFs STAT1 and IRF1. Integration of ChIP-Seq data confirms the binding of GATA2/3 and MSX2 on the majority of MER41-derived enhancers in human trophoblast stem cells (TSCs). Notably, the usb-family composition of MER41-derived enhancers that are active in human TSCs are distinct from those activated upon interferon stimulation, which is determined by the binding of trophoblast TFs. We further demonstrate that GATA2/3 and MSX2 have prevalent binding on numerous other ERV families – indicating their broad impact on ERV-derived placental enhancers. Functionally, the derepression of many syncytiotrophoblast genes after disruption of MSX2 is likely to be mediated by enhancers derived from ERVs – suggesting ERVs are also important for mediating transcriptional repression in human TSCs. Overall, this study characterized the prevalent binding of GATA2/3, MSX2 and their co-factors on ERV-derived enhancers in human TSCs and provided mechanistic insights into the importance of ERVs in human trophoblast regulatory network.

ORGANISM(S): Homo sapiens

PROVIDER: GSE209540 | GEO | 2023/01/01

REPOSITORIES: GEO

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Regulation of endogenous retrovirus-derived regulatory elements by GATA2/3 and MSX2 in human trophoblast stem cells (RNA-seq)

Project description:The placenta is an organ with extraordinary phenotypic diversity in eutherian mammals. Recent evidence suggest that numerous human placental enhancers are evolved from lineage-specific insertions of endogenous retroviruses (ERVs), yet the transcription factors (TFs) underlying their regulation remain largely elusive. Here, by first focusing on MER41, a primate-specific ERV family previously linked to placenta and innate immunity, we uncover the binding motifs of multiple crucial trophoblast TFs (GATA2/3, MSX2, GRHL2) in addition to innate immuninty TFs STAT1 and IRF1. Integration of ChIP-Seq data confirms the binding of GATA2/3 and MSX2 on the majority of MER41-derived enhancers in human trophoblast stem cells (TSCs). Notably, the usb-family composition of MER41-derived enhancers that are active in human TSCs are distinct from those activated upon interferon stimulation, which is determined by the binding of trophoblast TFs. We further demonstrate that GATA2/3 and MSX2 have prevalent binding on numerous other ERV families – indicating their broad impact on ERV-derived placental enhancers. Functionally, the derepression of many syncytiotrophoblast genes after disruption of MSX2 is likely to be mediated by enhancers derived from ERVs – suggesting ERVs are also important for mediating transcriptional repression in human TSCs. Overall, this study characterized the prevalent binding of GATA2/3, MSX2 and their co-factors on ERV-derived enhancers in human TSCs and provided mechanistic insights into the importance of ERVs in human trophoblast regulatory network.

2023-01-01 | GSE209536 | GEO

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Unraveling the role of human TSC-specific TFs [ChIP-Seq]

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Endogenous retrovirus MER50-derived enhancers confer the transcriptional regulation of human trophoblast syncytialization [RNA-Seq]

Project description:Multinucleated syncytiotrophoblasts (STBs), which are in direct contact with maternal blood, constitute the maternal-fetal interface critical for nutrient allocation, hormone production and immunological modulation during pregnancy. However, the genetic and epigenetic regulatory mechanisms governing trophoblast syncytialization remain largely elusive. We delineate that endogenous retroviruses (ERVs), which have been exapted as regulatory sequences for specific functional adaptations in placenta, profoundly rewire transcriptional program of trophoblast syncytialization. Here, we first determined dynamic bivalent ERV-derived enhancers with dual occupancy of H3K9me3 and H3K27ac in human trophoblast stem cells (hTSCs), which emerge as cell specific regulators of gene expression with markedly resolved H3K9me3 during differentiation towards STBs. Of note, bivalent enhancers derived from the Simiiformes-specific MER50 transposons were linked to a cluster of STB-specific genes. Importantly, depletions of MER50 elements adjacent to several STB genes, including MFSD2A, TNFAIP2 and RAI14, significantly attenuated their expression concomitant to dysregulated syncytium formation. Together, we propose that ERV-derived enhancers, MER50 specifically, fine-tune the transcriptional program accounting for human trophoblast syncytialization, which sheds light on novel epigenetic regulatory mechanisms underlying placental development.

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Endogenous retrovirus MER50-derived enhancers confer the transcriptional regulation of human trophoblast syncytialization [ChIP-Seq]

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TRIM28 repression of retrotransposon-based enhancers is necessary to preserve transcriptional dynamics in embryonic stem cells

Project description:TRIM28 (KAP1 - KRAB-associated protein 1) is critical for the silencing of endogenous retroviruses (ERVs) in embryonic stem (ES) cells. Here, we reveal that an essential impact of this process is the protection of cellular gene expression in early embryos from perturbation by cis-acting activators contained within these genetic invaders. In TRIM28-depleted ES cells, repressive chromatin marks at ERVs are replaced by histone modifications typical of active enhancers, stimulating transcription of nearby cellular genes, notably those harboring bivalent promoters. Correspondingly, ERV-derived sequences can repress or enhance expression from an adjacent promoter in transgenic embryos depending on their TRIM28-sensitivity in ES cells. TRIM28-mediated control of ERVs is therefore crucial not just to prevent retrotransposition, but more broadly to safeguard the transcriptional dynamics of early embryos. Analyses of transcriptional profiles and chromatin state in TRIM28 WT and KO cells

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Super-enhancer-guided decoding of gene regulatory networks in trophoblast stem cells

Project description:Cells belonging to trophoblast lineage are required for proper implantation and placentation, as well as the vascular, hematopoietic, and immunological properties of the placenta, a crucial organ mediating dynamic interactions between maternal and fetal tissues. Defects in trophoblast lineage development can cause early pregnancy failure or other pregnancy-related disorders. Despite its pivotal roles, the placenta remains as one of the least studied organs. Until now, only a handful of trophoblast-specific transcription factors (TFs) have been characterized, and underlying regulatory mechanisms modulating trophoblast lineage development remain poorly understood. Here we explore trophoblast stem cell (TSC)-specific super-enhancers (SEs) and subsequently identify SE-associated factors enriched with previously known and many unknown TFs modulating trophoblast lineage development. By mapping direct targets of 28 TSC-specific TFs in TSCs, we construct highly intertwined transcriptional regulatory networks where TFs are co-regulated and linked with signaling pathways, and which function as cellular modules dedicated to trophoblast lineage development. Additionally, we reveal that TSC-specific TFs alter their target sites corresponding to the reshaped enhancers during TSC differentiation. These findings advance our understanding on placenta biology.

2019-09-25 | GSE110950 | GEO

Ssrp1 co-immunoprecipitation and mass spectrometry

Project description:Endogenous retroviruses (ERVs) were usually silenced by various histone modifications on histone H3 variants and respective histone chaperones in embryonic stem cells (ESCs). However, it is still unknown whether chaperones of other histones could repress ERVs. Here, we show that H2A/H2B histone chaperone FACT plays a critical role in silencing ERVs and ERV-derived cryptic promoters in ESCs. Loss of FACT component Ssrp1 activated MERVL whereas the re-introduction of Ssrp1 rescued the phenotype. Additionally, Ssrp1 interacted with MERVL and suppressed cryptic transcription of MERVL-fused genes. Remarkably, Ssrp1 interacted with and recruited H2B deubiquitinase Usp7 to Ssrp1 target genes. Suppression of Usp7 caused similar phenotypes as loss of Ssrp1. Furthermore, Usp7 acted by deubiquitinating H2Bub and thereby repressed the expression of MERVL-fused genes. Taken together, our study uncovers a unique mechanism by which FACT complex silences ERVs and ERV-derived cryptic promoters in ESCs.

2020-08-24 | PXD017351 | Pride

lnc-EAPV binding proteins in C57BL/6J BMDMs

Project description:Endogenous retroviruses (ERVs) are transposable elements that cause host genome instability and usually play deleterious roles such as tumorigenesis. Recent advances also suggest that this 'enemy within' may encode viral mimic to induce antiviral immune responses through viral sensors. Here, through whole genome RNA-seq we discovered a full-length ERV-derived long non-coding RNA (lncRNA), designated lnc-EPAV (ERV-derived lncRNA positively regulates antiviral responses), as a positive regulator of NF-κB signaling. Lnc-EPAV expression was rapidly up-regulated by viral RNA mimic or RNA viruses to facilitate the expression of RELA, an NF-κB subunit that plays a critical role in antiviral responses. In turn, RELA promoted the transcription of lnc-EPAV to form a positive feedback loop. Transcriptome analysis of lnc-EPAV-silenced macrophages, combined with gain- and loss-of-function experiments, showed that lnc-EPAV was critical for induction of type I interferon (IFN) and inflammatory cytokine expression by RNA viruses. Consistently, lnc-EPAV-deficient mice exhibited reduced expression of type I IFNs, and consequently increased viral loads and mortality following lethal RNA virus infection. Mechanistically, lnc-EPAV promoted expression of RELA by competitively binding to and displacing SFPQ, a transcriptional repressor of RELA. The binding between ERV-derived RNAs and SFPQ also existed in human cells. Altogether, our work demonstrates an alternative mechanism by which ERVs regulate antiviral immune responses.

2018-11-07 | PXD011577 | Pride

Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer [RNA-seq]

Project description:Cancer cells exhibit rewired transcriptional regulatory networks that promote tumor growth and survival. However, the processes that configure these pathological networks remain poorly understood. Through a pan-cancer epigenomic analysis, we found that primate-specific endogenous retroviruses (ERVs) are an abundant source of enhancers that mediate transcriptional dysregulation in cancer. In colorectal cancer and other epithelial tumors, AP1 signaling drives aberrant activation of enhancers derived from the primate-specific ERV family LTR10. CRISPR studies revealed that LTR10 elements control colorectal cancer-specific gene expression at multiple loci associated with tumorigenesis. Within the human population, individual LTR10 elements show extensive structural variation due to repeat instability of an internal variable number tandem repeat (VNTR) region that affects AP1 binding. Our findings reveal that ERV-derived enhancers link oncogenic signaling to transcriptional dysregulation and shape the evolution of cancer-specific regulatory networks.

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