Bach1 Regulates the Self-renewal and Mesendodermal Differentiation of Human Embryonic Stem Cells
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ABSTRACT:
PROVIDER: PRJNA454105 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7079900_1.fastq.gz | Fastqsanger.gz | |||
| SRR7079900_2.fastq.gz | Fastqsanger.gz | |||
| SRR7079901_1.fastq.gz | Fastqsanger.gz | |||
| SRR7079901_2.fastq.gz | Fastqsanger.gz | |||
| SRR7079902_1.fastq.gz | Fastqsanger.gz |
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Project description:Transcription factor Bach1 is a member of the alkaline leucine zipper protein family. Our results therefore highlight a critical role for Bach1 proteins in a regulatory network that integrates essential Wnt/β-catenin and nodal-Smad signaling to repress mesendodermal differentiation of pluripotent cells
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Project description:The transcription factor BTB and CNC homology 1 (Bach1) is expressed in the embryos of mice, but whether Bach1 regulates the self-renewal and early differentiation of human embryonic stem cells (hESCs) is unknown. We report that the deubiquitinase ubiquitin-specific processing protease 7 (Usp7) is a direct target of Bach1, that Bach1 interacts with Nanog, Sox2, and Oct4, and that Bach1 facilitates their deubiquitination and stabilization via the recruitment of Usp7, thereby maintaining stem cell identity and self-renewal. Bach1 also interacts with polycomb repressive complex 2 (PRC2) and represses mesendodermal gene expression by recruiting PRC2 to the genes' promoters. The loss of Bach1 in hESCs promotes differentiation toward the mesendodermal germ layers by reducing the occupancy of EZH2 and H3K27me3 in mesendodermal gene promoters and by activating the Wnt/β-catenin and Nodal/Smad2/3 signaling pathways. Our study shows that Bach1 is a key determinant of pluripotency, self-renewal, and lineage specification in hESCs.
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Project description:Previously, we identified the transcription factor Zfx as a key regulator of self-renewal in murine ESCs. Here we extend those findings to human ESCs. Zfx knockdown in hESCs hindered clonal growth and decreased colony size after serial replating. Zfx overexpression enhanced clone formation, increased colony size and decreased expression of differentiation-related genes in human ESCs. Zfx-overexpressing hESCs resisted spontaneous differentiation but could be directed to differentiate into endodermal and neural cell fates when provided with the appropriate cues. Thus, Zfx acts as a molecular rheostat regulating the balance between self-renewal and differentiation in hESCs, revealing the close evolutionary conservation of the self-renewal mechanisms in murine and human ESCs. Human embryonic stem cells with over expression of ZFX were compared to the original cell line (H9) and a clonally derived wild-type cell line (clone 3)
2012-01-01 | E-GEOD-29784 | biostudies-arrayexpress
Project description:One of the most striking epigenetic alterations that occurs at the level of the nucleosome is the complete exchange of the canonical H2A histones for the macroH2A variant. Here, we provide insight in the function of this unique histone variant in embryonic and adult stem cells. Knockdown of macroH2A1 in mouse embryonic stem (mES) cells limited their capacity to differentiate but not their self-renewal. The loss of macroH2A1 interfered with the proper activation of differentiation genes, most of which are direct target genes of macroH2A. Additionally, macroH2A1-deficient mES cells displayed incomplete inactivation of pluripotency genes and formed defective embryoid bodies. In vivo, macroH2A1-deficient teratomas contained a massive expansion of malignant, undifferentiated carcinoma tissue. In the heterogeneous culture of primary human keratinocytes, macroH2A1 levels negatively correlated with the self-renewal capacity of the pluripotent compartment. Together these results establish macroH2A1 as a critical chromatin component that regulates the delicate balance between self-renewal and differentiation of embryonic and adult stem cells. Examination of the histone variant macroH2A1 in mouse Embryonic stem cells
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Project description:Embryonic stem cell (ESC) self-renewal and differentiation are governed by a broad-ranging regulatory network. Although the transcriptional regulatory mechanisms involved have been investigated extensively, post-transcriptional regulation is still poorly understood. Here we describe a critical role of the THO complex in ESC self-renewal and differentiation. We show that THO preferentially interacts with pluripotency gene transcripts through Thoc5, and is required for self-renewal at least in part by regulating their export and expression. During differentiation, THO loses its interaction with those transcripts due to reduced Thoc5 expression, leading to decreased expression of pluripotency proteins that facilitates exit from self-renewal. THO is also important for the establishment of pluripotency, as its depletion inhibits somatic cell reprogramming and blastocyst development. Together, our data indicate that THO regulates pluripotency gene mRNA export to control ESC self-renewal and differentiation, and therefore uncover a role for this aspect of post-transcriptional regulation in stem cell fate specification. mouse J1 cells were transfected with non-targeting (NT), Thoc2, and Thoc5 siRNAs. Total RNA was isolated 96 hours after transfection.
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Project description:Previously, we identified the transcription factor Zfx as a key regulator of self-renewal in murine ESCs. Here we extend those findings to human ESCs. Zfx knockdown in hESCs hindered clonal growth and decreased colony size after serial replating. Zfx overexpression enhanced clone formation, increased colony size and decreased expression of differentiation-related genes in human ESCs. Zfx-overexpressing hESCs resisted spontaneous differentiation but could be directed to differentiate into endodermal and neural cell fates when provided with the appropriate cues. Thus, Zfx acts as a molecular rheostat regulating the balance between self-renewal and differentiation in hESCs, revealing the close evolutionary conservation of the self-renewal mechanisms in murine and human ESCs.
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Project description:Cell lines geneticially engineered to undergo conditional asymmetric self-renewal were used to identify genes whose expression is asymmetric self-renewal associated (ASRA). Non-random sister chromatid segregation occurs concordantly with asymmetric self-renewal in these cell lines. Asymmetric self-renewal occurs when murine embryo fibroblasts that are otherwise p53-null are induced to express physiological levels of wildtype p53 protein (Asym). To distinguish p53-responsive genes that also require induction of asymmetric self renewal (i.e., ASRA genes) and/or non-random sister chromatid segregation for change, an additional control cell line, which continues to symmetrically self-renew (with random sister chromatid segregation) even when p53 is induced, was also compared (Symp53). This congenic cell line constitutively expresses the type II inosine monophosphate dehydrogenase (IMPDH II; the rate-limiting enzmye for guanine ribonucleotide biosynthesis) and, thereby, prevents p53-induced asymmetric self-renewal and non-random sister chromatid segregation. Three biological replicates of asymmetrically self-renewing cultures (Asym1-3) were compared with cultures that were symmetrically self-renewing - either because they did not express p53 (3 biological replicates, Sym1-3) or they expressed constitutive IMPDH II (i.e., not regulated by p53) as well as p53 (2 biological replicates, Symp53_1 and 2.)
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Project description:Stem cells (SC) exhibit a unique capacity for self-renewal in an undifferentiated state. It is unclear whether the self-renewal of pluripotent embryonic SC (ESC) and of tissue-specific adult SC such as hematopoietic SC (HSC) is controlled by common mechanisms. The deletion of transcription factor Zfx impaired the self-renewal but not the differentiation capacity of murine ESC; conversely, Zfx overexpression facilitated ESC self-renewal by opposing differentiation. Furthermore, Zfx deletion abolished the maintenance of adult bone marrow HSC, but did not affect erythromyeloid progenitors or fetal HSC. In both ESC and HSC, Zfx activated a common set of direct target genes. In addition, the loss of Zfx resulted in the induction of immediate-early and/or stress-inducible genes in both SC types but not in their differentiated progeny. These studies identify the first shared transcriptional regulator of ESC and HSC, suggesting a common molecular basis of self-renewal in embryonic and adult SC. Keywords: Global gene expression data analysis in Zfx-deficient murine ESC and HSC
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2023-10-19 | E-MTAB-12390 | biostudies-arrayexpress
Project description:Human exploration of outer space will inevitably require human reproduction and development in the space environment. Embryonic stem cells (ESCs) are widely employed to study mammalian development and reproduction for their characteristics of indefinite self-renewal and pluripotency. Due to the lack of experimental opportunities and related techniques, studies of the effects of microgravity on the self-renewal and differentiation of ESCs are mostly descriptive, with in-depth mechanistic studies remaining scarce. Here we show in both mouse and human ESCs that simulated microgravity (SMG)-induced stress regulates the self-renewal and pluripotency in a conserved mechanism. Specifically, SMG upregulates the expression of heat shock protein (HSP) and/or HSF1 genes, thereby increasing the expression of core pluripotency factors and the activity of the Wnt pathway. In mESCs, the upregulation of Hsps and Hsf1 genes by SMG increased the activity of the LIF/STAT3 pathway. The upregulation of Tbx3 by increased activity of the Wnt and LIF/STAT3 pathways promotes the differentiation of both mouse and human ESCs to mesendoderm under the SMG environment. Finally, the ATAC-seq and ChIP-seq analysis in this study reveal a minor effect of SMG on the global chromatin accessibility and the overall patterns of the tested histone modifications in mESCs.
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