The Dynamics of Transcriptional Activation by Hepatic Reprogramming Factors

Horisawa, Kenichi; Udono, Miyako; Ueno, Kazuko; Ohkawa, Yasuyuki; Nagasaki, Masao; Sekiya, Sayaka; Suzuki, Atsushi

doi:10.1016/j.molcel.2020.07.012

Cited by 52 publications

(39 citation statements)

References 59 publications

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“…Repression of neural stemness by these factors is achieved by binding to genes whose expression is enriched in embryonic neural cells, repressing transcription of neural enriched genes. Meanwhile, they activate genes that confer the property of non-neural cells, for example, the activation of liver-specific genes by FOXA3 (Horisawa et al, 2020) and activation of epithelial gene CDH1 by HHEX in the present study. Functioning as both a transcriptional repressor and an activator might be a general feature of prodifferentiation transcription factors (Abate-Shen et al, 2008;Gaston et al, 2016).…”

Section: Discussionsupporting

confidence: 52%

Suppression of Cell Tumorigenicity by Non-neural Pro-differentiation Factors via Inhibition of Neural Property in Tumorigenic Cells

Yang

Cao

Chen

et al. 2021

Front. Cell Dev. Biol.

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Our studies have demonstrated that cell tumorigenicity and pluripotent differentiation potential stem from neural stemness or a neural ground state, which is defined by a regulatory network of higher levels of machineries for basic cell physiological functions, including cell cycle, ribosome biogenesis, protein translation, spliceosome, epigenetic modification factors, reprogramming factors, etc., in addition to the neural stemness specific factors. These machineries and neural stemness factors mostly play cancer-promoting roles. It can be deduced that differentiation requires the repression of neural ground state and causes the reduction or loss of neural ground state and thus tumorigenicity in tumorigenic cells. Formerly, we showed that neuronal differentiation led to reduced tumorigenicity in tumorigenic cells. In the present study, we show that non-neural pro-differentiation factors, such as GATA3, HNF4A, HHEX, and FOXA3 that specify mesodermal or/and endodermal tissues during vertebrate embryogenesis, suppress tumorigenicity via repression of neural stemness and promotion of non-neural property in tumorigenic cells. Mechanistically, these transcription factors repress the transcription of neural enriched genes and meanwhile activate genes that specify non-neural properties via direct binding to the promoters of these genes. We also show that combined expression of HHEX and FOXA3 suppresses tumorigenesis effectively in the AOM/DSS model of colitis-associated cancer. We suggest that targeting the property of neural stemness could be an effective strategy for cancer therapy.

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Section: Discussionsupporting

confidence: 52%

Suppression of Cell Tumorigenicity by Non-neural Pro-differentiation Factors via Inhibition of Neural Property in Tumorigenic Cells

Yang

Cao

Chen

et al. 2021

Front. Cell Dev. Biol.

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“…For instance, SOX8 is reported to play a role in embryonic development, but also participates in neuronal cell fate determination in a transient and time-dependent manner [ 31 ]. Additionally, transcription factors in this category included those with a role in non-neuronal/endothelial cell phenotypes, for example FOXA3 with a role in establishing hepatic cell fate and ETV1, which is reported to participate in the establishment of His–Purkinje system development [ 32 , 33 ]. This category also included genes for factors that function as repressors of other transcription factors, or partner with some factors that are required for maintaining pluripotency.…”

Section: Resultsmentioning

confidence: 99%

In Silico Analysis to Explore Lineage-Independent and -Dependent Transcriptional Programs Associated with the Process of Endothelial and Neural Differentiation of Human Induced Pluripotent Stem Cells

Nakhaei‐Nejad

Trinity

Jabbari

et al. 2021

JCM

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Despite a major interest in understanding how the endothelial cell phenotype is established, the underlying molecular basis of this process is not yet fully understood. We have previously reported the generation of induced pluripotent stem cells (iPS) from human umbilical vein endothelial cells and differentiation of the resulting HiPS back to endothelial cells (Ec-Diff), as well as neural (Nn-Diff) cell lineage that contained both neurons and astrocytes. Furthermore, the identities of these cell lineages were established by gene array analysis. Here, we explored the same arrays to gain insight into the gene alteration processes that accompany the establishment of endothelial vs. non-endothelial neural cell phenotypes. We compared the expression of genes that code for transcription factors and epigenetic regulators when HiPS is differentiated into these endothelial and non-endothelial lineages. Our in silico analyses have identified cohorts of genes that are similarly up- or downregulated in both lineages, as well as those that exhibit lineage-specific alterations. Based on these results, we propose that genes that are similarly altered in both lineages participate in priming the stem cell for differentiation in a lineage-independent manner, whereas those that are differentially altered in endothelial compared to neural cells participate in a lineage-specific differentiation process. Specific GATA family members and their cofactors and epigenetic regulators (DNMT3B, PRDM14, HELLS) with a major role in regulating DNA methylation were among participants in priming HiPS for lineage-independent differentiation. In addition, we identified distinct cohorts of transcription factors and epigenetic regulators whose alterations correlated specifically with the establishment of endothelial vs. non-endothelial neural lineages.

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“…Successful reprogramming of embryonic or adult fibroblasts has been reported by the co-overexpression of FoxA3, GATA4, and HNF1α [4] or HNF4α, together with either FoxA isoform [5] or HNF1β with FoxA3 [6]. Studies on the abovetype of "induced-Hepatocytes" (iHep cells) have demonstrated the need for co-operation between these factors to induce hepatic targets [7].…”

Section: Liver Developmentmentioning

confidence: 99%

Transcription Control of Liver Development

Tachmatzidi

Galanopoulou

Talianidis

2021

Cells

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During liver organogenesis, cellular transcriptional profiles are constantly reshaped by the action of hepatic transcriptional regulators, including FoxA1-3, GATA4/6, HNF1α/β, HNF4α, HNF6, OC-2, C/EBPα/β, Hex, and Prox1. These factors are crucial for the activation of hepatic genes that, in the context of compact chromatin, cannot access their targets. The initial opening of highly condensed chromatin is executed by a special class of transcription factors known as pioneer factors. They bind and destabilize highly condensed chromatin and facilitate access to other “non-pioneer” factors. The association of target genes with pioneer and non-pioneer transcription factors takes place long before gene activation. In this way, the underlying gene regulatory regions are marked for future activation. The process is called “bookmarking”, which confers transcriptional competence on target genes. Developmental bookmarking is accompanied by a dynamic maturation process, which prepares the genomic loci for stable and efficient transcription. Stable hepatic expression profiles are maintained during development and adulthood by the constant availability of the main regulators. This is achieved by a self-sustaining regulatory network that is established by complex cross-regulatory interactions between the major regulators. This network gradually grows during liver development and provides an epigenetic memory mechanism for safeguarding the optimal expression of the regulators.

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The Dynamics of Transcriptional Activation by Hepatic Reprogramming Factors

Cited by 52 publications

References 59 publications

Suppression of Cell Tumorigenicity by Non-neural Pro-differentiation Factors via Inhibition of Neural Property in Tumorigenic Cells

Suppression of Cell Tumorigenicity by Non-neural Pro-differentiation Factors via Inhibition of Neural Property in Tumorigenic Cells

In Silico Analysis to Explore Lineage-Independent and -Dependent Transcriptional Programs Associated with the Process of Endothelial and Neural Differentiation of Human Induced Pluripotent Stem Cells

Transcription Control of Liver Development

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