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- Hashimoto, K, et al.
(author)
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Embryonic LTR retrotransposons supply promoter modules to somatic tissues
- 2021
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In: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 31:11, s. 1983-1993
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Journal article (peer-reviewed)abstract
- Long terminal repeat (LTR) retrotransposons are widely distributed across the human genome. They have accumulated through retroviral integration into germline DNA and are latent genetic modules. Active LTR promoters are observed in germline cells; however, little is known about the mechanisms underlying their active transcription in somatic tissues. Here, by integrating our previous transcriptome data set with publicly available data sets, we show that the LTR families MLT2A1 and MLT2A2 are primarily expressed in human four-cell and eight-cell embryos and are also activated in some adult somatic tissues, particularly pineal gland. Three MLT2A elements function as the promoters and first exons of the protein-coding genes ABCE1, COL5A1, and GALNT13 specifically in the pineal gland of humans but not in that of macaques, suggesting that the exaptation of these LTRs as promoters occurred during recent primate evolution. This analysis provides insight into the possible transition from germline insertion to somatic expression of LTR retrotransposons.
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- Jouhilahti, EM, et al.
(author)
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The human PRD-like homeobox gene LEUTX has a central role in embryo genome activation
- 2016
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In: Development (Cambridge, England). - : The Company of Biologists. - 1477-9129 .- 0950-1991. ; 143:19, s. 3459-3469
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Journal article (peer-reviewed)abstract
- Leucine twenty homeobox gene (LEUTX) is a PAIRED (PRD)-like homeobox gene that is expressed nearly exclusively in human preimplantation embryos. We previously identified a novel transcription start site for the predicted human LEUTX gene based on the transcriptional analysis of human preimplantation embryos. The novel variant encodes a protein with a complete homeodomain. Here we provide a detailed description of the molecular cloning of the complete homeodomain-containing LEUTX. Using a human embryonic stem cell overexpression model we show that the complete homeodomain isoform is functional and sufficient to activate the transcription of a large fraction of the genes found upregulated in human embryo genome activation, whereas the previously predicted partial homeodomain isoform is largely inactive. Another PRD-like transcription factor, DPRX, appears as a powerful repressor of transcription. We propose a two-stage model of human EGA in which LEUTX acts as a transcriptional activator at 4-cell stage, and DPRX as a balancing repressor at 8-cell stage. We conclude that LEUTX is a candidate regulator of human embryo genome activation.
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- Katayama, S, et al.
(author)
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Phylogenetic and mutational analyses of human LEUTX, a homeobox gene implicated in embryogenesis
- 2018
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 17421-
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Journal article (peer-reviewed)abstract
- Recently, human PAIRED-LIKE homeobox transcription factor (TF) genes were discovered whose expression is limited to the period of embryo genome activation up to the 8-cell stage. One of these TFs is LEUTX, but its importance for human embryogenesis is still subject to debate. We confirmed that human LEUTX acts as a TAATCC-targeting transcriptional activator, like other K50-type PAIRED-LIKE TFs. Phylogenetic comparisons revealed that Leutx proteins are conserved across Placentalia and comprise two conserved domains, the homeodomain, and a Leutx-specific domain containing putative transcriptional activation motifs (9aaTAD). Examination of human genotype resources revealed 116 allelic variants in LEUTX. Twenty-four variants potentially affect function, but they occur only heterozygously at low frequency. One variant affects a DNA-specificity determining residue, mutationally reachable by a one-base transition. In vitro and in silico experiments showed that this LEUTX mutation (alanine to valine at position 54 in the homeodomain) results in a transactivational loss-of-function to a minimal TAATCC-containing promoter and a 36 bp motif enriched in genes involved in embryo genome activation. A compensatory change in residue 47 restores function. The results support the notion that human LEUTX functions as a transcriptional activator important for human embryogenesis.
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- Krjutskov, K, et al.
(author)
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Globin mRNA reduction for whole-blood transcriptome sequencing
- 2016
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 31584-
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Journal article (peer-reviewed)abstract
- The transcriptome analysis of whole-blood RNA by sequencing holds promise for the identification and tracking of biomarkers; however, the high globin mRNA (gmRNA) content of erythrocytes hampers whole-blood and buffy coat analyses. We introduce a novel gmRNA locking assay (GlobinLock, GL) as a robust and simple gmRNA reduction tool to preserve RNA quality, save time and cost. GL consists of a pair of gmRNA-specific oligonucleotides in RNA initial denaturation buffer that is effective immediately after RNA denaturation and adds only ten minutes of incubation to the whole cDNA synthesis procedure when compared to non-blood RNA analysis. We show that GL is fully effective not only for human samples but also for mouse and rat and so far incompletely studied cow, dog and zebrafish.
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- Madissoon, E, et al.
(author)
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Characterization and target genes of nine human PRD-like homeobox domain genes expressed exclusively in early embryos
- 2016
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 28995-
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Journal article (peer-reviewed)abstract
- PAIRED (PRD)-like homeobox genes belong to a class of predicted transcription factor genes. Several of these PRD-like homeobox genes have been predicted in silico from genomic sequence but until recently had no evidence of transcript expression. We found recently that nine PRD-like homeobox genes, ARGFX, CPHX1, CPHX2, DPRX, DUXA, DUXB, NOBOX, TPRX1 and TPRX2, were expressed in human preimplantation embryos. In the current study we characterized these PRD-like homeobox genes in depth and studied their functions as transcription factors. We cloned multiple transcript variants from human embryos and showed that the expression of these genes is specific to embryos and pluripotent stem cells. Overexpression of the genes in human embryonic stem cells confirmed their roles as transcription factors as either activators (CPHX1, CPHX2, ARGFX) or repressors (DPRX, DUXA, TPRX2) with distinct targets that could be explained by the amino acid sequence in homeodomain. Some PRD-like homeodomain transcription factors had high concordance of target genes and showed enrichment for both developmentally important gene sets and a 36 bp DNA recognition motif implicated in Embryo Genome Activation (EGA). Our data implicate a role for these previously uncharacterized PRD-like homeodomain proteins in the regulation of human embryo genome activation and preimplantation embryo development.
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