Comprehensive characterization of the embryonic factor LEUTX

Gawriyski, Lisa; Jouhilahti, Eeva-Mari; Yoshihara, Masahito; Fei, Liangru; Weltner, Jere; Airenne, Tomi T.; Trokovic, Ras; Bhagat, Shruti; Tervaniemi, Mari H.; Murakawa, Yuji; Salokas, Kari; Liu, Xiaonan; Miettinen, Sini; Bürglin, Thomas R.; Sahu, Biswajyoti; Otonkoski, Timo; Johnson, Mark S.; Katayama, Shintaro; Varjosalo, Markku; Kere, Juha

doi:10.1016/j.isci.2023.106172

Cited by 8 publications

(18 citation statements)

References 91 publications

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“…Alternatively, H3.X/Y and LETUX may contribute to further upregulation of DUX4 though there is no strong evidence that they directly upregulate the DUX4 gene. 56 , 71 Thus, in this case, the effect may be indirect, for example through upregulation of MDB3L. 67 , 68 Taken together, our results strongly suggest that DUX4 triggers the sequential induction of epigenetic regulators and downstream transcription factors to ensure a “coherent feedforward effect” 72 on the DUX4 gene network ( Figure 7 C).…”

Section: Discussionmentioning

confidence: 61%

Engineered FSHD mutations results in D4Z4 heterochromatin disruption and feedforward DUX4 network activation

Kong,

Nguyen,

et al. 2024

iScience

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Section: Discussionmentioning

confidence: 61%

Engineered FSHD mutations results in D4Z4 heterochromatin disruption and feedforward DUX4 network activation

Kong,

Nguyen,

et al. 2024

iScience

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“…SERPINE2, MYDGF, NCOA3, SMCHD1, CCNL1 and PTAR1 are highly correlated with the LEUTX group rather than the ZSCAN4 group (Figure 6C, middle), whereas LOLX2 and SOX9 are positively correlated with the ZSCAN4 group. SERPINE2 is identified as a LEUTX target gene (Gawriyski et al 2023) and NCOA3 protein was found to interact with LEUTX protein (Gawriyski et al 2023), supporting the connection. SOX9 has been shown to be up-regulated by DUX4, but the mechanism is unclear (Resnick et al 2019).…”

Section: Gene Co-expression Analysis Of Dux4 Target Genes Identifies ...mentioning

confidence: 79%

Single-cell spatial transcriptomics reveals a dystrophic trajectory following a developmental bifurcation of myoblast cell fates in facioscapulohumeral muscular dystrophy

Chen,

Kong,

Johnston

et al. 2024

Genome Res.

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Facioscapulohumeral muscular dystrophy (FSHD) is linked to abnormal de-repression of the transcription activator DUX4. This effect is localized to a low percentage of cells, requiring single-cell analysis. However, single-cell/nucleus RNA-seq cannot fully capture the transcriptome of multinucleated large myotubes. To circumvent these issues, we use MERFISH (Multiplexed Error Robust Fluorescent In Situ Hybridization) spatial transcriptomics that allows profiling of RNA transcripts at a subcellular resolution. We simultaneously examined spatial distributions of 140 genes, including 24 direct DUX4 targets, in in vitro differentiated control, isogenic D4Z4 contraction mutant and FSHD patient myotubes and unfused mononuclear cells (MNCs), as well as the individual nuclei within them. We find myocyte nuclei segregate into 2 clusters defined by expression of DUX4 target genes, which is exclusively found in patient/mutant nuclei, while MNCs cluster based on developmental state. Patient/mutant myotubes are found in "FSHD-hi" and "FSHD-lo" states with the former signified by high DUX4 target expression and decreased muscle gene expression. Pseudotime analyses reveal a clear bifurcation of myoblast differentiation into control and FSHD-hi myotube branches, with variable numbers of DUX4 target expressing nuclei found in multinucleated FSHD-hi myotubes. Gene coexpression modules related to extracellular matrix and stress gene ontologies are significantly altered in patient/mutant myotubes compared to control. We also identify distinct subpathways within the DUX4 gene network that may differentially contribute to the disease transcriptomic phenotype. Taken together, our MERFISH-based study provides effective gene network profiling of multinucleated cells and identifies FSHD-induced transcriptomic alterations during myoblast differentiation.

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“…9aaTADs have previously been reported in all Yamanaka factors (Piskacek et al, 2021 ) and many other TFs (Piskacek et al, 2020 ). In LEUTX, the C-terminal 9aaTAD has been shown to facilitate stable interaction with EP300 and CBP (Gawriyski et al, 2023 ). Similarly, the tumor protein p53 has a TAD that facilitates its interaction with CBP and EP300, and directly affects its transcriptional regulatory potential (Teufel et al, 2007 ; Feng et al, 2009 ).…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that BioID-MS and AP-MS can detect high-confidence interactors and identify human transcription factors (Göös et al, 2022 ) and employed these to study the ETCHbox family member LEUTX (Gawriyski et al, 2023 ). Here, we applied our MAC-tag-based BioID-MS method (Liu et al, 2018; Liu et al, 2020 ) for ARGFX, DPRX, TPRX1, TPRX2 and CRX, OTX1, and OTX2 in Flp-In™ T-REx™ 293 cells.…”

Section: Resultsmentioning

confidence: 99%

“…The PRDL binding site was shown to be enriched in the promoters of 4- and 8-cell stage EGA gene promoters (Töhönen et al, 2015 ) and in 8-cell stage enhancer regions (Xia et al, 2019 ). Our protein of interest (bait) set also included DPPA3 , a direct transcriptional regulation target of LEUTX (Gawriyski et al, 2023 ); the preimplantation TFs EGR2, ZNF263 , and KLF3 (Leng et al, 2019 ); and ZSCAN4 (Töhönen et al, 2015 ; Hendrickson et al, 2017 ). PITX2 and GSC are lineage-specific markers for meso- and endoderm, and mesendoderm, respectively, and are activated in 8CLCs (Mazid et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Interaction network of human early embryonic transcription factors

Gawriyski,

Tan,

Liu

et al. 2024

EMBO Rep

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Embryonic genome activation (EGA) occurs during preimplantation development and is characterized by the initiation of de novo transcription from the embryonic genome. Despite its importance, the regulation of EGA and the transcription factors involved in this process are poorly understood. Paired-like homeobox (PRDL) family proteins are implicated as potential transcriptional regulators of EGA, yet the PRDL-mediated gene regulatory networks remain uncharacterized. To investigate the function of PRDL proteins, we are identifying the molecular interactions and the functions of a subset family of the Eutherian Totipotent Cell Homeobox (ETCHbox) proteins, seven PRDL family proteins and six other transcription factors (TFs), all suggested to participate in transcriptional regulation during preimplantation. Using mass spectrometry-based interactomics methods, AP-MS and proximity-dependent biotin labeling, and chromatin immunoprecipitation sequencing we derive the comprehensive regulatory networks of these preimplantation TFs. By these interactomics tools we identify more than a thousand high-confidence interactions for the 21 studied bait proteins with more than 300 interacting proteins. We also establish that TPRX2, currently assigned as pseudogene, is a transcriptional activator.

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Comprehensive characterization of the embryonic factor LEUTX

Cited by 8 publications

References 91 publications

Engineered FSHD mutations results in D4Z4 heterochromatin disruption and feedforward DUX4 network activation

Engineered FSHD mutations results in D4Z4 heterochromatin disruption and feedforward DUX4 network activation

Single-cell spatial transcriptomics reveals a dystrophic trajectory following a developmental bifurcation of myoblast cell fates in facioscapulohumeral muscular dystrophy

Interaction network of human early embryonic transcription factors

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