Enforcement of developmental lineage specificity by transcription factor Oct1

Shen, Zuolian; Kang, Jinsuk; Shakya, Arvind; Tabaka, Marcin; Jarboe, Elke A.; Regev, Aviv; Tantin, Dean

doi:10.7554/elife.20937

Cited by 18 publications

(39 citation statements)

References 54 publications

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“…In a recent study, Shen et al. (2017) found that mammalian POU2F1/OCT1 and POU5F1/OCT4 occupy both overlapping and independent sets of target genes in ESCs and their daughters.…”

Section: Discussionmentioning

confidence: 99%

“…(2017) found that mammalian POU2F1/OCT1 and POU5F1/OCT4 occupy both overlapping and independent sets of target genes in ESCs and their daughters. Importantly, concomitant with the loss of OCT4 binding, OCT1 occupancy increased during differentiation ( Shen et al., 2017 ). This implies that POU/OCT factors may act in succession to regulate developmental processes based on sequential binding to common targets.…”

Section: Discussionmentioning

confidence: 99%

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The POU/Oct Transcription Factor Nubbin Controls the Balance of Intestinal Stem Cell Maintenance and Differentiation by Isoform-Specific Regulation

et al. 2018

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SummaryDrosophila POU/Oct transcription factors are required for many developmental processes, but their putative regulation of adult stem cell activity has not been investigated. Here, we show that Nubbin (Nub)/Pdm1, homologous to mammalian OCT1/POU2F1 and related to OCT4/POU5F1, is expressed in gut epithelium progenitor cells. We demonstrate that the nub-encoded protein isoforms, Nub-PB and Nub-PD, play opposite roles in the regulation of intestinal stem cell (ISC) maintenance and differentiation. Depletion of Nub-PB in progenitor cells increased ISC proliferation by derepression of escargot expression. Conversely, loss of Nub-PD reduced ISC proliferation, suggesting that this isoform is necessary for ISC maintenance, analogous to mammalian OCT4/POU5F1 functions. Furthermore, Nub-PB is required in enteroblasts to promote differentiation, and it acts as a tumor suppressor of Notch RNAi-driven hyperplasia. We suggest that a dynamic and well-tuned expression of Nub isoforms in progenitor cells is required for maintaining gut epithelium homeostasis.

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“…In a recent study, Shen et al. (2017) found that mammalian POU2F1/OCT1 and POU5F1/OCT4 occupy both overlapping and independent sets of target genes in ESCs and their daughters.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The POU/Oct Transcription Factor Nubbin Controls the Balance of Intestinal Stem Cell Maintenance and Differentiation by Isoform-Specific Regulation

et al. 2018

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“…Although POU homeodomain proteins have been widely implicated in neuronal, immune cell, and stem cell development, the role of POU transcription factors during heart formation has remained elusive. In this regard, Oct4 has been implicated in mesoderm development, and a recent study found that Oct1 null ES cells failed to form beating cardiomyocytes upon directed differentiation (Li et al, ; Shen et al, ). However, aside from a single study examining the influence of mPou/Emb/Pou6f1 on cardiac alpha actinin gene expression, very little is known about the potential role of Pou6f1/ pouC during cardiac morphogenesis (Molinari et al, ).…”

Section: Discussionmentioning

confidence: 99%

pouC Regulates Expression of bmp4 During Atrioventricular Canal Formation in Zebrafish

Bhakta

Padanad

Harris

et al. 2018

Developmental Dynamics

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Background Many human gene mutations have been linked to congenital heart disease (CHD), yet CHD remains a major health issue worldwide due in part to an incomplete understanding of the molecular basis for cardiac malformation. Results Here we identify the orthologous mouse Pou6f1 and zebrafish pouC as POU homeodomain transcription factors enriched in the developing heart. We find that pouC is a multi‐functional transcriptional regulator containing separable activation, repression, protein–protein interaction, and DNA binding domains. Using zebrafish heart development as a model system, we demonstrate that pouC knockdown impairs cardiac morphogenesis and affects cardiovascular function. We also find that levels of pouC expression must be fine‐tuned to enable proper heart formation. At the cellular level, we demonstrate that pouC knockdown disrupts atrioventricular canal (AVC) cardiomyocyte maintenance, although chamber myocyte specification remains intact. Mechanistically, we show that pouC binds a bmp4 intronic regulatory element to mediate transcriptional activation. Conclusions Taken together, our study establishes pouC as a novel transcriptional input into the regulatory hierarchy that drives AVC morphogenesis in zebrafish. We anticipate that these findings will inform future efforts to explore functional conservation in mammals and potential association with atrioventricular septal defects in humans. Developmental Dynamics 248:173‐188, 2019. © 2018 Wiley Periodicals, Inc.

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“…We compared this group of genes with Oct1 targets identified in T cells [18] and with Oct1/Oct4 targets identified in embryonic stem cells (ESCs, [46]. Oct4 levels are far higher than Oct1 in ESCs, resulting in most targets being occupied exclusively by Oct4, which has similar DNA binding specificity [46]. Of the 17 identified genes whose expression correlates with the tumor model, 8 were previously identified as direct Oct1 targets in T cells and 9 as Oct4 targets in ESCs ( Fig 5C).…”

Section: Genes That Are Differentially Expressed Between Chemical Andmentioning

confidence: 99%

Oct1/Pou2f1 is selectively required for gut regeneration and regulates gut malignancy

Vázquez-Arreguín

Bensard

et al. 2018

Preprint

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The transcription factor Oct1/Pou2f1 promotes poised gene expression states, mitotic stability, glycolytic metabolism and other characteristics of stem cell potency. To determine the effect of Oct1 loss on stem cell maintenance and malignancy, we deleted Oct1 in two different mouse gut stem cell compartments. Oct1 deletion preserved homeostasis in vivo and the ability to generate cultured organoids in vitro, but blocked the ability to regenerate after treatment with dextran sodium sulfate, and the ability to maintain organoids after passage. In a chemical model of colon cancer, loss of Oct1 in the colon severely restricted tumorigenicity. In contrast, loss of one or both Oct1 alleles progressively increased tumor burden in a colon cancer model driven by loss of heterozygosity of the tumor suppressor gene Apc. The different outcomes are consistent with prior findings that Oct1 promotes mitotic stability, and consistent with different gene expression signatures associated with the two models. These results reveal that Oct1 is selectively required for gut regeneration, and has potent effects in colon malignancy, with outcome (pro-oncogenic or tumor suppressive) dictated by tumor etiology. Author summaryColorectal cancer is the second leading cause of cancer death in the United States. Approximately 35% of diagnosed patients eventually succumb to disease. The high incidence and mortality due to colon cancer demand a better understanding of factors controlling the physiology and pathophysiology of the gastrointestinal tract. Previously, we and others showed that the widely expressed transcription factor is expressed at higher protein levels in stem cells, including intestinal stem cells. In this study we use a conditional mouse Oct1 (Pou2f1) allele deleted in two different intestinal stem cell compartments. The results indicate that Oct1 loss is dispensable for maintenance of the mouse gut, but required for regeneration. We also tested Oct1 loss in the context of two different mouse colon cancer models. We find that Oct1 loss has opposing effects in the two models, and further that the two models are associated with different gene expression signatures. The differentially expressed genes are enriched for previously identified Oct1 targets, suggesting that differential gene control by Oct1 is one mechanism underlying different outcomes.

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Enforcement of developmental lineage specificity by transcription factor Oct1

Cited by 18 publications

References 54 publications

The POU/Oct Transcription Factor Nubbin Controls the Balance of Intestinal Stem Cell Maintenance and Differentiation by Isoform-Specific Regulation

The POU/Oct Transcription Factor Nubbin Controls the Balance of Intestinal Stem Cell Maintenance and Differentiation by Isoform-Specific Regulation

pouC Regulates Expression of bmp4 During Atrioventricular Canal Formation in Zebrafish

Oct1/Pou2f1 is selectively required for gut regeneration and regulates gut malignancy

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