Gene Targeting Study Reveals Unexpected Expression of Brain-expressed X-linked 2 in Endocrine and Tissue Stem/Progenitor Cells in Mice

Ito, Keiichi; Yamazaki, Satoshi; Yamamoto, Ryō; Tajima, Yoko; Yanagida, Akira; Kobayashi, Toshihiro; Kato-Itoh, Megumi; Kakuta, Shigeru; Iwakura, Yoichiro; Nakauchi, Hiromitsu; Kamiya, Akihide

doi:10.1074/jbc.m114.580084

Cited by 23 publications

(24 citation statements)

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“…In further agreement with a functional role of Bex2 during reprogramming, its OE in het/het MEFs greatly improved reprogramming efficiency (Figure 5H, right). Finally, we confirmed that established Tfap2c and Bex2 KO iPSC clones appear normal (Figure S6E), consistent with reports indicating that both genes are dispensable for embryonic stem cell (ESC) maintenance (Auman et al, 2002; Ito et al, 2014; Schemmer et al, 2013). We conclude that Tfap2c is critical for reprogramming whereas Bex2 enhances reprogramming but is not absolutely required.…”

Section: Resultssupporting

confidence: 90%

“…Furthermore, Tfap2c OE resulted in a striking increase in the fraction of Eff intermediates as well as Oct4 -GFP + cells at d6 (Figure 5I). To corroborate the functional role of Bex2 in reprogramming, we infected Bex2 KO or littermate control MEFs (Ito et al, 2014) with LV- Stemcca . Contrary to our siRNA results, we found no difference in the number of iPSC-like colonies (Figure S6D).…”

Section: Resultsmentioning

confidence: 99%

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Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming

et al. 2018

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Cellular reprogramming converts differentiated cells into induced pluripotent stem cells (iPSCs). However, this process is typically very inefficient, complicating mechanistic studies. We identified and molecularly characterized rare, early intermediates poised to reprogram with up to 95% efficiency, without perturbing additional genes or pathways, during iPSC generation from mouse embryonic fibroblasts. Analysis of these cells uncovered transcription factors (e.g., Tfap2c and Bex2) that are important for reprogramming but dispensable for pluripotency maintenance. Additionally, we observed striking patterns of chromatin hyperaccessibility at pluripotency loci, which preceded gene expression in poised intermediates. Finally, inspection of these hyperaccessible regions revealed an early wave of DNA demethylation that is uncoupled from de novo methylation of somatic regions late in reprogramming. Our study underscores the importance of investigating rare intermediates poised to produce iPSCs, provides insights into reprogramming mechanisms, and offers a valuable resource for the dissection of transcriptional and epigenetic dynamics intrinsic to cell fate change.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming

et al. 2018

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“…The BEX2 gene is highly expressed in the human embryonic brain and have a regulatory role in embryonic development ( Han et al, 2005 ). A study of mice liver gene expression revealed a strong expression of BEX2 in stem/progenitor cells ( Ito et al, 2014 ). Further, BEX2 is a downstream molecule of the mammalian target of rapamycin (mTOR) signaling pathway ( Hu et al, 2015 ) that can regulate lipogenesis and ketogenesis in liver ( Laplante and Sabatini, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

STAT6, PBX2, and PBRM1 Emerge as Predicted Regulators of 452 Differentially Expressed Genes Associated With Puberty in Brahman Heifers

et al. 2018

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The liver plays a central role in metabolism and produces important hormones. Hepatic estrogen receptors and the release of insulin-like growth factor 1 (IGF1) are critical links between liver function and the reproductive system. However, the role of liver in pubertal development is not fully understood. To explore this question, we applied transcriptomic analyses to liver samples of pre- and post-pubertal Brahman heifers and identified differentially expressed (DE) genes and genes encoding transcription factors (TFs). Differential expression of genes suggests potential biological mechanisms and pathways linking liver function to puberty. The analyses identified 452 DE genes and 82 TF with significant contribution to differential gene expression by using a regulatory impact factor metric. Brain-derived neurotrophic factor was observed as the most down-regulated gene (P = 0.003) in post-pubertal heifers and we propose this gene influences pubertal development in Brahman heifers. Additionally, co-expression network analysis provided evidence for three TF as key regulators of liver function during pubertal development: the signal transducer and activator of transcription 6, PBX homeobox 2, and polybromo 1. Pathway enrichment analysis identified transforming growth factor-beta and Wnt signaling pathways as significant annotation terms for the list of DE genes and TF in the co-expression network. Molecular information regarding genes and pathways described in this work are important to further our understanding of puberty onset in Brahman heifers.

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“…Furthermore, this population was marked by strong expression of CDH2, BEX5, SSH and PLA2G2A, all of which have been previously linked to stem cell potential. For example, CDH2 was linked to regulation of cell fate decision in the mesodermal lineage (Alimperti and Andreadis, 2015), and SHH to initiation of villus formation in the developing mouse intestine (Shyer et al, 2015), while BEX family genes were found to be expressed in tissue stem/progenitor cells (Ito et al, 2014). Although this cell type was found to be rapidly cycling, their transcriptional profile differed distinctly from LGR5+ epithelial cells, which were found to be present in small numbers at 6 PCW.…”

Section: Single Cell Transcriptomic Profile Of Epithelial Progenitor mentioning

confidence: 99%

Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease

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et al. 2020

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Human gut development requires the orchestrated interaction of various differentiating cell types. Here we generate an in-depth single-cell map of the developing human intestine at 6-10 weeks post-conception, a period marked by crypt-villus formation. Our analysis reveals the transcriptional profile of cycling epithelial precursor cells, which are distinct from LGR5expressing cells. We use computational analyses to show that these cells contribute to differentiated cell subsets directly and indirectly via the generation of LGR5-expressing stem cells and receive signals from the surrounding mesenchymal cells. Furthermore, we draw parallels between the transcriptomes of ex vivo tissues and in vitro fetal organoids, revealing the maturation of organoid cultures in a dish. Lastly, we compare scRNAseq profiles from paediatric Crohn's disease epithelium alongside matched healthy controls to reveal disease associated changes in epithelial composition. Contrasting these with the fetal profiles reveals re-activation of fetal transcription factors in Crohn's disease epithelium. Our study provides a unique resource, available at www.gutcellatlas.org, and underscores the importance of unravelling fetal development in understanding disease.

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Gene Targeting Study Reveals Unexpected Expression of Brain-expressed X-linked 2 in Endocrine and Tissue Stem/Progenitor Cells in Mice

Cited by 23 publications

References 50 publications

Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming

Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming

STAT6, PBX2, and PBRM1 Emerge as Predicted Regulators of 452 Differentially Expressed Genes Associated With Puberty in Brahman Heifers

Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease

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