The pluripotent stem cell-specific transcript ESRG is dispensable for human pluripotency

Takahashi, Kazutoshi; Nakamura, Michiko; Okubo, Chikako; Kliesmete, Zane; Ohnuki, Mari; Narita, Megumi; Watanabe, Akira; Ueda, Mai; Takashima, Yasuhiro; Hellmann, Ines; Yamanaka, Shinya

doi:10.1371/journal.pgen.1009587

Cited by 21 publications

(18 citation statements)

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“…As such, these experiments have primarily, if not exclusively targeted 7up elements. While the role of individual 7up copies in the maintenance of pluripotency of primed cells remains to be clarified (Takahashi et al, 2021), our work highlights potential additional roles of other LTR7 subfamilies in naïve, formative ESCs. Of relevance to this issue is our finding that elements of the 7u2 subfamily are highly and exclusively expressed in the pluripotent epiblast in vivo (Fig.…”

Section: Implications For Stem Cell and Regenerative Biologymentioning

confidence: 88%

“…These results converge on the notion that HERVH products (RNA or proteins) exert some modulatory effect on the cellular homeostasis of pluripotent stem cells. However, it is important to emphasize that different HERVH knockdown constructs produced variable results and inconsistent phenotypes ( Lu et al, 2014 ; Wang et al, 2014 ; Zhang et al, 2019 ), and a recent knockout experiment of the most highly transcribed locus ( ESRG ) failed to recapitulate its previous knockdown phenotype ( Takahashi et al, 2021 ). These inconsistent results have failed to clarify which expressed HERVH loci, if any, are necessary for the maintenance of pluripotency.…”

Section: Introductionmentioning

confidence: 99%

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Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo

Carter

Singh

Dumbović

et al. 2022

eLife

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The human endogenous retrovirus type-H (HERVH) family is expressed in the preimplantation embryo. A subset of these elements are specifically transcribed in pluripotent stem cells where they appear to exert regulatory activities promoting self-renewal and pluripotency. How HERVH elements achieve such transcriptional specificity remains poorly understood. To uncover the sequence features underlying HERVH transcriptional activity, we performed a phyloregulatory analysis of the long terminal repeats (LTR7) of the HERVH family, which harbor its promoter, using a wealth of regulatory genomics data. We found that the family includes at least 8 previously unrecognized subfamilies that have been active at different timepoints in primate evolution and display distinct expression patterns during human embryonic development. Notably, nearly all HERVH elements transcribed in ESCs belong to one of the youngest subfamilies we dubbed LTR7up. LTR7 sequence evolution was driven by a mixture of mutational processes, including point mutations, duplications, and multiple recombination events between subfamilies, that led to transcription factor binding motif modules characteristic of each subfamily. Using a reporter assay, we show that one such motif, a predicted SOX2/3 binding site unique to LTR7up, is essential for robust promoter activity in induced pluripotent stem cells. Together these findings illuminate the mechanisms by which HERVH diversified its expression pattern during evolution to colonize distinct cellular niches within the human embryo.

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Section: Implications For Stem Cell and Regenerative Biologymentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo

Carter

Singh

Dumbović

et al. 2022

eLife

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“…Indirect immunocytochemistry was performed as described previously ( Takahashi et al., 2021 ). The cells were washed once with D-PBS and fixed using 4% paraformaldehyde for 15 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

A stress-reduced passaging technique improves the viability of human pluripotent cells

Takahashi

Okubo

Nakamura

et al. 2022

Cell Reports Methods

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“…More than 3,000 DNA sequences derived from insertions of the human endogenous retrovirus type H (HERVH) are scattered across human genome at fixed non-polymorphic locations (Thomas et al, 2018). The long terminal repeats designated LTR7 harbor the promoter sequence of the HERVH and the HERVH/LTR7 family has been extensively investigated in the context of its regulatory functions and locus-specific differential expression in human preimplantation embryogenesis, human embryonic and pluripotent stem cells (Fort et al, 2014; Gemmell et al, 2015; Glinsky et al, 2018; Göke et al,2015; Izsvák et al, 2016; Kelley and Rinn, 2012; Loewer et al, 2010; Lu et al, 2014; Ohnuki et al, 2014; Pontis et al, 2019; Römer et al, 2017; Santoni et al, 2012; Takahashi et al, 2021 Theunissen et al, 2016; Wang et al, 2014; Zhang et al, 2019),…”

Section: Introductionmentioning

confidence: 99%

Molecular diversity and phenotypic pleiotropy of genomic regulatory loci derived from human endogenous retrovirus type H (HERVH) promoter LTR7 and HERVK promoter LTR5_Hs and their impacts on pathophysiology of Modern Humans

Glinsky

2022

Preprint

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Targeted DNA sequences conservation analyses of 17 primate species demonstrated that human endogenous retroviruses (HERV) LTR7/HERVH and LTR5_Hs/HERVK appear to have distinct evolutionary histories charted by evidence of the earliest presence and expansion of highly-conserved (HC) LTR sequences. HC-LTR7 loci were mapped to genomes of Old World Monkeys (18% of all HC-LTR7 loci), suggesting that LTR7/HERVH have entered germlines of primates in Africa after the separation of the New World Monkey lineage. HC-LTR5_Hs loci have been identified in the Gibbon’s genome (24% of all HC-LTR5_Hs loci), suggesting that LTR5_Hs/HERVK successfully colonized primates’ germlines after the segregation of Gibbons’ species. Subsequently, both LTR7 and LTR5_Hs undergo a marked ∼4-5-fold expansion in genomes of Great Apes. Timelines of quantitative expansion of both LTR7 and LTR5_Hs loci during evolution of Great Apes appear to replicate the consensus evolutionary sequence of increasing cognitive and behavioral complexities of non-human primates, which seems particularly striking for LTR7 loci and 11 distinct LTR7 subfamilies.Consistent with previous reports, identified in this study 351 human-specific (HS) insertions of LTR7 (175 loci) and LTR5_Hs (176 loci) regulatory sequences have been linked to genes implicated in establishment and maintenance of naïve and primed pluripotent states and preimplantation embryogenesis phenotypes. Unexpectedly, HS regulatory LTRs appear linked with genes encoding markers of 12 distinct cells’ populations of fetal gonads, as well as genes implicated in physiology and pathology of human spermatogenesis, including Y-linked spermatogenic failure, oligo- and azoospermia.Granular investigations of genes linked with eleven LTR7 subfamilies revealed that mammalian offspring survival (MOS) genes seem to remain one of consistent regulatory targets throughout ∼30 MYA of the divergent evolution of LTR7 loci. Differential GSEA of MOS versus non-MOS genes identified clearly discernable dominant enrichment patterns of phenotypic traits affected by MOS genes linked with LTR7 (562 MOS genes) and LTR5_Hs (126 MOS genes) regulatory loci across the large panel of genomics and proteomics databases reflecting a broad spectrum of human physiological and pathological traits. GSEA of LTR7-linked MOS genes identified more than 2200 significantly enriched records of human common and rare diseases and gene signatures of 466 significantly enriched records of Human Phenotype Ontology traits, including 92 genes of Autosomal Dominant Inheritance and 93 genes of Autosomal Recessive Inheritance.One of the most informative categories of genes linked with LTR7 elements were genes implicated in functional and morphological features of central nervous system, including genes regulating synaptic transmission and protein-protein interactions at synapses, as well as gene signatures differentially regulated in cells of distinct neurodevelopmental stages and morphologically diverse cell types residing and functioning in human brain. These include Neural Stem/Precursor cells, Radial Glia cells, Bergman Glia cells, Pyramidal cells, Tanycytes, Immature neurons, Interneurons, Trigeminal neurons, GABAergic neurons, and Glutamatergic neurons. GSEA of LTR7-linked regulatory targets identified significantly enriched sets of genes encoding markers of more than 80 specialized types of neurons and markers of 521 human brain regions, most prominently, subiculum and dentate gyrus amongst top significantly enriched records. These observations were validated and extended by identification and characterization of 1944 genes comprising high-fidelity down-steam regulatory targets of LTR7 and/or LTR5_Hs loci, which are markedly enriched for genes implicated in neoplasm metastasis, intellectual disability, autism, multiple cancer types, Alzheimer’s, schizophrenia, and other brain disorders. Despite distinct evolutionary histories of retroviral LTRs, genes representing down-stream regulatory targets of LTR7 and LTR5_Hs elements exert the apparently cooperative and exceedingly broad phenotypic impacts on human physiology and pathology. Observations reported in this contribution highlight the need to accelerate the in-depth experimental and translational explorations of these important genomic determinants of Modern Humans’ health and disease states.

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The pluripotent stem cell-specific transcript ESRG is dispensable for human pluripotency

Cited by 21 publications

References 64 publications

Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo

Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo

A stress-reduced passaging technique improves the viability of human pluripotent cells

Molecular diversity and phenotypic pleiotropy of genomic regulatory loci derived from human endogenous retrovirus type H (HERVH) promoter LTR7 and HERVK promoter LTR5_Hs and their impacts on pathophysiology of Modern Humans

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