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Endogenous retroviruses reshape early development of human-animal chimeras [RNA-seq]

ABSTRACT: Interspecies chimeras can illuminate the causes of embryonic evolution and open the possibility of a new era of regenerative medicine growing human organs in large animals. Currently, however, available human pluripotent stem cells (hPSCs) are inefficient at generating human-animal chimeras for reasons unknown. Here, we reveal the diverse roles of primate-specific endogenous retroviruses in early development of human-mouse chimeras thereby greatly improving efficiency, leading to the first birth of live chimeras. By optimizing culture conditions, we generate a novel hPSC line mimicking human preimplantation epiblast with improved interspecies chimeric competency. This stem cell line is characterized by the hyper-transcription of primate-specific human endogenous retrovirus-H (HERVH). The human-specific protein ESRG, derived from HERVH, represses de novo LINE-1 retrotransposition so safeguarding hPSC genome stability and improving the developmental ability and chimeric ratio of preimplantation embryos. In addition, the human-specific endogenous retrovirus-K (HERVK(HML2)) released from hPSCs affects mouse trophectoderm, and impairs placentation, resulting in compromised implantation of human-mouse chimeras. Antiretroviral treatment on hPSCs for a short time before injection into mouse embryos, rescues the placentation of chimeric embryos and improves their implantation. Taken together, our study reveals the important but diverse roles of endogenous retroviruses in interspecies chimerism, and provides a strategy to overcome developmental obstacles in human-animal chimeric embryos.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168420 | GEO | 2026/03/01

REPOSITORIES: GEO

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Endogenous retroviruses reshape early development of human-animal chimeras

Project description:The experiments to demonstrate interspecies chimerism open the possibility of a new era of regenerative medicine growing human organs in large animals. However, currently available human pluripotent stem cells (hPSCs) are inefficient at generating human-animal chimeras for reasons unknown, indicating that developmental obstacles need to be overcome. Here, we uncover the diverse roles of primate-specific endogenous retroviruses in early development of human-mouse chimeras. By optimizing culture conditions, we generate a novel hPSC line mimicking human preimplantation epiblast with improved interspecies chimeric competency. This stem cell line is characterized by the hyper-transcription of primate-specific human endogenous retrovirus-H (HERVH). The human-specific protein ESRG, derived from HERVH, represses de novo L1 retrotransposition to safeguard hPSC genome stability that improves the developmental ability and chimeric ratio of preimplantation embryos. However, in contrast, the human-specific endogenous retrovirus-K (HERVK) released from hPSCs affects mouse trophectoderm, and impairs placentation, resulting in compromised implantation of human-mouse chimeras. Antiretroviral treatment on hPSCs for a short time before injection into mouse embryos, rescues the placentation of chimeric embryos with implantation frequency improved. Taken together, our study reveals the important but diverse roles of endogenous retroviruses in interspecies chimerism, and provides a strategy to overcome developmental obstacles in human-animal chimeric embryos.

2026-03-01 | GSE168228 | GEO

Endogenous retroviruses reshape early development of human-animal chimeras [ATAC-seq]

Project description:Interspecies chimeras can illuminate the causes of embryonic evolution and open the possibility of a new era of regenerative medicine growing human organs in large animals. Currently, however, available human pluripotent stem cells (hPSCs) are inefficient at generating human-animal chimeras for reasons unknown. Here, we reveal the diverse roles of primate-specific endogenous retroviruses in early development of human-mouse chimeras thereby greatly improving efficiency, leading to the first birth of live chimeras. By optimizing culture conditions, we generate a novel hPSC line mimicking human preimplantation epiblast with improved interspecies chimeric competency. This stem cell line is characterized by the hyper-transcription of primate-specific human endogenous retrovirus-H (HERVH). The human-specific protein ESRG, derived from HERVH, represses de novo LINE-1 retrotransposition so safeguarding hPSC genome stability and improving the developmental ability and chimeric ratio of preimplantation embryos. In addition, the human-specific endogenous retrovirus-K (HERVK(HML2)) released from hPSCs affects mouse trophectoderm, and impairs placentation, resulting in compromised implantation of human-mouse chimeras. Antiretroviral treatment on hPSCs for a short time before injection into mouse embryos, rescues the placentation of chimeric embryos and improves their implantation. Taken together, our study reveals the important but diverse roles of endogenous retroviruses in interspecies chimerism, and provides a strategy to overcome developmental obstacles in human-animal chimeric embryos.

2026-03-01 | GSE168419 | GEO

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Project description:Functional-assay limitations are an emerging issue in characterizing human pluripotent stem cells (hPSCs). With rodent PSCs, chimera formation, using pre-implantation embryos, is the gold-standard assay of pluripotency. In hPSCs, this can only be monitored via teratoma formation or in vitro differentiation, as ethical concerns preclude generation of human-animal chimera. To circumvent this issue, we established a functional assay utilizing interspecific blastocyst injection and in vitro culture (interspecies in vitro chimera assay). The assay uses mouse pre-implantation embryos and human PSCs to make interspecies chimeras cultured in vitro to the early egg cylinder stage. When hiPSCs, both conventional and naive type, which called M-bM-^@M-^\reset cellM-bM-^@M-^], were injected into mouse embryos and cultured. The cells were never integrated into the epiblast of egg cylinder stage-embryo. These results suggest that hPSCs, including naM-CM-/ve type, are unable to form chimera with mouse embryo. Reset cells were converted from conventional human iPSC line PB004, and then compared their gene expression profile with or without transgene overexpression induced by doxycyclin treatment.

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2015-03-10 | GSE66657 | GEO

ZBTB12-HERVH-LncRNA axis is a molecular barrier for dedifferentiation of human stem cells

Project description:Development is generally viewed as one-way traffic of cell state transition from primitive to developmentally advanced states. However, molecular mechanisms that ensure the unidirectional transition remain largely unknown. NanoCAGE sequencing identified an evolutionarily conserved zinc finger repressor, ZBTB12, as a molecular barrier for dedifferentiation of human pluripotent stem cells (hPSCs). Single cell RNA sequencing revealed that ZBTB12 is essential for three germ layer differentiation by blocking hPSC dedifferentiation. Mechanistically, ZBTB12 serves as a master repressor of human endogenous retrovirus H (HERVH). Active HERVH loci drive the expression of overlapping long non-coding RNAs (lncRNAs) whose downregulation by ZBTB12 is necessary for pluripotency exit and lineage derivation. Overall, we have identified a ZBTB12-HERVH-lncRNA axis as molecular machinery that safeguards the unidirectional transition of stem cell fates.

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RNA-Seq after knockdown of the endogeneous retrovirus HERVH in human embryonic stem cells

Project description:Human endogenous retrovirus subfamily H (HERVH) is a class of transposable elements whose members are expressed preferentially in human pluripotent stem cells. Here, we report that the long-terminal repeat regions of HERVH function as enhancers which are regulated by OCT4. Strikingly, we found that HERVH is a nuclear-localized long non-coding RNA that is required to maintain the undifferentiated state of human embryonic stem cells. Furthermore, we showed that HERVH is associated with OCT4 and co-activators such as P300, CBP and mediator subunits. Together, these results uncover a new and unexpected role of species-specific transposable elements in specifying the pluripotency of human cells.

2014-03-30 | E-MTAB-2072 | biostudies-arrayexpress

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Project description:The purpose of this study to examine the effect of Calbindin expression, driven by an upstream HERVH LTR (human endogenous retrovirus H long terminal repeat), in HARA squamous lung cancer cells. Parental HARA cells, Calbindin-deficient HARA 3D5 cells, HARA.LTR7-GFP+ and HARA.LTR7-GFP- cells were compared and were processed as a single batch, using the 10× Genomics Chromium platform.

2023-08-01 | E-MTAB-11550 | biostudies-arrayexpress

Podocalyxin-Like Protein 1 Regulates Extended and Primed Pluripotency through the Cholesterol Biosynthesis Pathway

Project description:We utilized scRNA-seq to study the human-mouse chimera transcriptomic regulation at peri-implantation embryo stage. Single-cell RNA sequencing revealed PODXL overexpression boosted chimerism between human cells in mouse host embryos and the potential cell-cell communication interactions in human-mouse chimeras. Potential cell-cell communications were identified to optimize cell-cell contact interaction for reducing the xenogeneic barrier in the interspecies chimeras in future studies.

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ARID1A loss derepresses human endogenous retrovirus-H to modulate BRD4-dependent transcription

Project description:Purpose: The transposable elements (TEs) through evolutionary exaptation have become an integral part of human genome, offering ample regulatory sequences and shaping chromatin 3D architecture. While the functional impacts of TE-derived sequences on early embryogenesis are recognized, their role in malignancy has only started to emerge. Results: Here we show that many TEs, especially the pluripotency-related endogenous retrovirus H (HERVH), are abnormally activated in colorectal cancer (CRC) samples. The transcriptional upregulation of HERVH is associated with mutations of several tumor suppressors including ARID1A. Knockout of ARID1A in CRC cells leads to increased accessibility at HERVH loci and enhanced transcription, which is dependent on ARID1B. Suppression of HERVH in CRC cells and patient-derived organoids impairs tumor growth. Mechanistically, HERVH transcripts colocalize with nuclear BRD4 foci, modulate their dynamics, and co-regulate many target genes. Conclusions: Altogether, we uncover a critical role for ARID1A in restraining HERVH, which can promote tumorigenesis by stimulating BRD4-dependent transcription when ARID1A is mutated.

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