Phylogenetic and mutational analyses of human LEUTX, a homeobox gene implicated in embryogenesis

Katayama, Shintaro; Ranga, Vipin; Jouhilahti, Eeva-Mari; Airenne, Tomi T.; Johnson, Mark S.; Mukherjee, Krishanu; Bürglin, Thomas R.; Kere, Juha

doi:10.1038/s41598-018-35547-5

Cited by 19 publications

(36 citation statements)

References 84 publications

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“…We identify several arrays of tandem ETCHbox duplicates, one of the largest of which is an array of LEUTX loci in O. cuniculus . Previous work detected six loci (Katayama et al 2018 ), whereas we detect 27 gene copies in the assembly analysed, of which 14 are putatively functional, 11 are putative pseudogenes and two are of uncertain functional status (Online Resource Fig. S1).…”

Section: Resultsmentioning

confidence: 75%

“…However, this analysis was limited by sparse phylogenetic coverage and the low-quality genome assemblies available at the time. Katayama et al ( 2018 ) performed a deeper analysis of LEUTX evolution, but this study was restricted to the one gene and without analysis of gene loss. Recent improvements to long-read DNA sequencing mean that many additional mammalian genome sequences are now available, assembled to high contiguity and accuracy.…”

Section: Introductionmentioning

confidence: 99%

“…The causes and consequences of ETCHbox genes’ dynamic evolution are yet to be elucidated. It has been proposed that their dynamism may be driven by a possible role in the evolution of reproductive traits in mammals, such as placentation, which is highly variable between eutherians (Maeso et al 2016 ), or due to selection in some lineages for shorter gestation times (Katayama et al 2018 ). Alternatively, the genes’ dynamic evolution may be a consequence of partial functional redundancy, which would cause relaxed selection on loss-of-function mutations, or distributed robustness, where the perturbation of one part of a system (loss of a gene) is compensated by non-redundant parts (other genes) (Wagner 2005 ; Royall et al 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Dynamic Molecular Evolution of Mammalian Homeobox Genes: Duplication, Loss, Divergence and Gene Conversion Sculpt PRD Class Repertoires

2021

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The majority of homeobox genes are highly conserved across animals, but the eutherian-specific ETCHbox genes, embryonically expressed and highly divergent duplicates of CRX, are a notable exception. Here we compare the ETCHbox genes of 34 mammalian species, uncovering dynamic patterns of gene loss and tandem duplication, including the presence of a large tandem array of LEUTX loci in the genome of the European rabbit (Oryctolagus cuniculus). Despite extensive gene gain and loss, all sampled species possess at least two ETCHbox genes, suggesting their collective role is indispensable. We find evidence for positive selection and show that TPRX1 and TPRX2 have been the subject of repeated gene conversion across the Boreoeutheria, homogenising their sequences and preventing divergence, especially in the homeobox region. Together, these results are consistent with a model where mammalian ETCHbox genes are dynamic in evolution due to functional overlap, yet have collective indispensable roles.

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Section: Resultsmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dynamic Molecular Evolution of Mammalian Homeobox Genes: Duplication, Loss, Divergence and Gene Conversion Sculpt PRD Class Repertoires

2021

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“…Nevertheless, colocalization of KDM4E with LEUTX expression in the same myotube is consistently better than with DUX4 expression (Figure 5d). Motif analyses revealed that the promoter region of the KDM4E gene contains not only the DUX4 binding motif but also multiple sites of the putative LEUTX binding motif (Figure S6) (Jouhilahti et al, 2016; Katayama et al, 2018). These results raise the possibility that LEUTX may be involved in KDM4E upregulation.…”

Section: Resultsmentioning

confidence: 99%

Relationship of DUX4 and target gene expression in FSHD myocytes

et al. 2021

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Facioscapulohumeral dystrophy (FSHD) is associated with the upregulation of the DUX4 transcription factor and its target genes. However, low‐frequency DUX4 upregulation in patient myocytes is difficult to detect and examining the relationship and dynamics of DUX4 and target gene expression has been challenging. Using RNAScope in situ hybridization with highly specific probes, we detect the endogenous DUX4 and target gene transcripts in situ in patient skeletal myotubes during 13‐day differentiation in vitro. We found that the endogenous DUX4 transcripts primarily localize as foci in one or two nuclei as compared with the accumulation of the recombinant DUX4 transcripts in the cytoplasm. We also found the continuous increase of DUX4 and target gene‐positive myotubes after Day 3, arguing against its expected immediate cytotoxicity. Interestingly, DUX4 and target gene expression become discordant later in differentiation with the increase of DUX4‐positive/target gene‐negative as well as DUX4‐negative/target gene‐positive myotubes. Depletion of DUX4‐activated transcription factors, DUXA and LEUTX, specifically repressed a DUX4‐target gene, KDM4E, later in differentiation, suggesting that after the initial activation by DUX4, target genes themselves contribute to the maintenance of downstream gene expression. Together, the study provides important new insights into the dynamics of the DUX4 transcriptional network in FSHD patient myocytes.

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“…DUX4 comprises two homeodomains and an intrinsically disordered region with three regions of predicted low disorder conserved in primates. Two predicted amphipathic helices contain a nine amino acid transactivation domain (9aaTAD 20 ), also present in LEUTX 21 , and a motif known to recruit the KIX domain 22 of the cAMP-response element binding protein (CREB)-binding protein (CBP) 23 (Fig. 4a).…”

Section: Resultsmentioning

confidence: 99%

DUX4 regulates oocyte to embryo transition in human

Vuoristo

Hydén-Granskog

Yoshihara

et al. 2019

Preprint

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45During the human oocyte-to-embryo transition, the fertilized oocyte undergoes 46 final maturation and the embryo genome is gradually activated during the first 47 three cell divisions. How this transition is coordinated in humans is largely 48 unknown. We show that the double homeodomain transcription factor DUX4 49 contributes to this transition. DUX4 knockdown in human zygotes caused 50 insufficient transcriptome reprogramming as observed three days after 51 fertilization. Induced DUX4 expression in human embryonic stem cells activated 52 transcription of thousands of newly identified bi-directional transcripts, including 53 putative enhancers for embryonic genome activation genes such as LEUTX. DUX4 54 protein interacted with transcriptional modifiers that are known to couple 55 enhancers and promoters. Taken together, our results reveal that DUX4 is a 56 pioneer regulating oocyte-to-embryo transition in human through activation of 57 intergenic genome, especially enhancers, and hence setting the stage for early 58 human embryo development. 59 60 61 62 63 64 65 4 Mammalian pre-implantation development commences with oocyte-to-embryo 66 transition, which involves fundamental changes in the epigenetic landscapes, 67 modulation of cell cycle control, and translation or clearance of selected maternal 68 mRNAs, culminating to embryonic genome activation 1,2 . The pioneer regulators 69 orchestrating the oocyte-to-embryo transition and first embryo genome activation steps 70 in human remain poorly understood. The conserved double homeodomain transcription 71factor DUX4 represents a plausible candidate regulating the oocyte-to-embryo 72 transition in humans, given its capacity to activate germline genes and genomic repeat 73 elements 3-5 . Here we show that DUX4 is able to launch the first reprogramming steps 74 from oocyte to embryo in human by activating thousands of novel enhancers and 75 therein, modulating the transcriptome and chromatin. Human DUX4 knockdown 76 embryos are viable until the third day of development, but their transcriptome is 77 severely altered. Our proteomics approaches suggest that DUX4 binds to Mediator 78 complex and chromatin modifiers through its C-terminal domains, providing a likely 79 explanation to how DUX4 may extensively modulate the genome. This study implies a 80 wider role for DUX4 as a cellular gate keeper acting both as a general genomic modifier 81 of cell fate as well as a specific inducer of first wave embryo genome activation genes. 82 83Results 84 Quantification of DUX4 in human embryos 85The DUX4 induced gene network is highly conserved 6 and recent reports showed that 86 DUX4 is expressed in early human embryos 3,4 . However, details of this dynamic 87 process, including initiation of DUX4 expression, remained ambiguous. Therefore, we 88Given the short-term and precise manifestation of DUX4 mRNA and protein in human 107 zygotes and early cleavage stage embryos, we next asked how DUX4 regulates the first 108 steps of human embryo development. We microinjected either DUX4...

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Phylogenetic and mutational analyses of human LEUTX, a homeobox gene implicated in embryogenesis

Cited by 19 publications

References 84 publications

Dynamic Molecular Evolution of Mammalian Homeobox Genes: Duplication, Loss, Divergence and Gene Conversion Sculpt PRD Class Repertoires

Dynamic Molecular Evolution of Mammalian Homeobox Genes: Duplication, Loss, Divergence and Gene Conversion Sculpt PRD Class Repertoires

Relationship of DUX4 and target gene expression in FSHD myocytes

DUX4 regulates oocyte to embryo transition in human

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