scholarly journals Super-enhancer-guided mapping of regulatory networks controlling mouse trophoblast stem cells

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Bum-Kyu Lee ◽  
Yu jin Jang ◽  
Mijeong Kim ◽  
Lucy LeBlanc ◽  
Catherine Rhee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Regulatory Networks ◽  
Expression Patterns ◽  
Cell Types ◽  
Regulatory Mechanisms ◽  
Trophoblast Stem Cells ◽  
Healthy Pregnancy ◽  
Trophoblast Stem ◽  
Super Enhancer ◽  
Transcriptional Regulatory

Abstract Trophectoderm (TE) lineage development is pivotal for proper implantation, placentation, and healthy pregnancy. However, only a few TE-specific transcription factors (TFs) have been systematically characterized, hindering our understanding of the process. To elucidate regulatory mechanisms underlying TE development, here we map super-enhancers (SEs) in trophoblast stem cells (TSCs) as a model. We find both prominent TE-specific master TFs (Cdx2, Gata3, and Tead4), and >150 TFs that had not been previously implicated in TE lineage, that are SE-associated. Mapping targets of 27 SE-predicted TFs reveals a highly intertwined transcriptional regulatory circuitry. Intriguingly, SE-predicted TFs show 4 distinct expression patterns with dynamic alterations of their targets during TSC differentiation. Furthermore, depletion of a subset of TFs results in dysregulation of the markers for specialized cell types in placenta, suggesting a role during TE differentiation. Collectively, we characterize an expanded TE-specific regulatory network, providing a framework for understanding TE lineage development and placentation.

scholarly journals Relationships between homeoprotein EGAM1C and the expression of the placental prolactin gene family in mouse placentae and trophoblast stem cells

Reproduction ◽  
2011 ◽  
Vol 141 (2) ◽  
pp. 259-268 ◽  
Author(s):  
Koichi Saito ◽  
Atsushi Ogawa ◽  
Kyoko Toyofuku ◽  
Yusuke Hosoi ◽  
Miki Soma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Family ◽  
Expression Patterns ◽  
Embryonic Stem ◽  
Cell Types ◽  
Culture Conditions ◽  
Expression Levels ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Prl Gene

The mouse Crxos gene encodes three structurally related homeoproteins, EGAM1, EGAM1N, and EGAM1C, as transcription and splicing variants. Recently, we identified the functions of EGAM1 and EGAM1N in the regulation of differentiation in mouse embryonic stem cells. However, the function of EGAM1C remains unknown. To explore the additional roles of these proteins, the ontogenic expression of the respective mRNAs in post implantation mouse embryos and extraembryonic tissues, particularly from embryonic day (E) 10.5 to E18.5, was analyzed. The expression of Egam1n mRNA was specifically detected in embryos throughout this period, whereas that of Egam1 was undetectable in any of the tissues examined. However, in the placenta, Egam1c mRNA and its encoded protein were detected after E16.5, and these expression levels increased by E18.5 immediately before partum. Quantitative RT-PCR and in situ hybridization analyses in placentae revealed that the spatial and temporal expression patterns of the Egam1c mRNA were related to some extent with those of Prl3a1 and Prl5a1 and partially overlapped that of Prl3b1, which are members of the placental prolactin (PRL) gene family. When EGAM1C was overexpressed moderately in mouse trophoblast stem cells as a model for undifferentiated and differentiating placental cell types, the expression levels of endogenous Prl3b1 and Prl5a1 were enhanced under both undifferentiated and differentiating culture conditions. These results indicated that EGAM1C may play a role in the expression of members of the placental PRL gene family, such as Prl3b1 and Prl5a1.

scholarly journals Context-Dependent Wiring of Sox2 Regulatory Networks for Self-Renewal of Embryonic and Trophoblast Stem Cells

2013 ◽  
Vol 52 (3) ◽  
pp. 380-392 ◽  
Author(s):  
Kenjiro Adachi ◽  
Itoshi Nikaido ◽  
Hiroshi Ohta ◽  
Satoshi Ohtsuka ◽  
Hiroki Ura ◽  
...  
Keyword(s):  
Stem Cells ◽  
Regulatory Networks ◽  
Self Renewal ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Context Dependent

scholarly journals BAP1/ASXL complex modulation regulates epithelial-mesenchymal transition during trophoblast differentiation and invasion

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Vicente Perez-Garcia ◽  
Georgia Lea ◽  
Pablo Lopez-Jimenez ◽  
Hanneke Okkenhaug ◽  
Graham J Burton ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial Mesenchymal Transition ◽  
Expression Patterns ◽  
Normal Function ◽  
Trophoblast Differentiation ◽  
Human Trophoblast ◽  
Mesenchymal Transition ◽  
Trophoblast Stem Cells ◽  
Endogenous Expression ◽  
Trophoblast Stem

Normal function of the placenta depends on the earliest developmental stages when trophoblast cells differentiate and invade into the endometrium to establish the definitive maternal-fetal interface. Previously, we identified the ubiquitously expressed tumour suppressor BRCA1-associated protein 1 (BAP1) as a central factor of a novel molecular node controlling early mouse placentation. However, functional insights into how BAP1 regulates trophoblast biology are still missing. Using CRISPR/Cas9 knockout and overexpression technology in mouse trophoblast stem cells, here we demonstrate that the downregulation of BAP1 protein is essential to trigger epithelial-mesenchymal transition (EMT) during trophoblast differentiation associated with a gain of invasiveness. Moreover, we show that the function of BAP1 in suppressing EMT progression is dependent on the binding of BAP1 to additional sex comb-like (ASXL1/2) proteins to form the polycomb repressive deubiquitinase (PR-DUB) complex. Finally, both endogenous expression patterns and BAP1 overexpression experiments in human trophoblast stem cells suggest that the molecular function of BAP1 in regulating trophoblast differentiation and EMT progression is conserved in mice and humans. Our results reveal that the physiological modulation of BAP1 determines the invasive properties of the trophoblast, delineating a new role of the BAP1 PR-DUB complex in regulating early placentation.

scholarly journals Highly rigid H3.1/H3.2–H3K9me3 domains set a barrier for cell fate reprogramming in trophoblast stem cells

2022 ◽  
Author(s):  
Masashi Hada ◽  
Hisashi Miura ◽  
Akie Tanigawa ◽  
Shogo Matoba ◽  
Kimiko Inoue ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Large Scale ◽  
Cell Types ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Genomic Reprogramming ◽  
Pluripotent Marker ◽  
High Degree

The placenta is a highly evolved, specialized organ in mammals. It differs from other organs in that it functions only for fetal maintenance during gestation. Therefore, there must be intrinsic mechanisms that guarantee its unique functions. To address this question, we comprehensively analyzed epigenomic features of mouse trophoblast stem cells (TSCs). Our genome-wide, high-throughput analyses revealed that the TSC genome contains large-scale (>1-Mb) rigid heterochromatin architectures with a high degree of histone H3.1/3.2–H3K9me3 accumulation, which we termed TSC-defined highly heterochromatinized domains (THDs). Importantly, depletion of THDs by knockdown of CAF1, an H3.1/3.2 chaperone, resulted in down-regulation of TSC markers, such as Cdx2 and Elf5, and up-regulation of the pluripotent marker Oct3/4, indicating that THDs maintain the trophoblastic nature of TSCs. Furthermore, our nuclear transfer technique revealed that THDs are highly resistant to genomic reprogramming. However, when H3K9me3 was removed, the TSC genome was fully reprogrammed, giving rise to the first TSC cloned offspring. Interestingly, THD-like domains are also present in mouse and human placental cells in vivo, but not in other cell types. Thus, THDs are genomic architectures uniquely developed in placental lineage cells, which serve to protect them from fate reprogramming to stably maintain placental function.

scholarly journals Human trophoblast stem cells: Real or not real?

Placenta ◽  
2017 ◽  
Vol 60 ◽  
pp. S57-S60 ◽  
Author(s):  
Ching-Wen Chang ◽  
Mana M. Parast
Keyword(s):  
Stem Cells ◽  
Human Trophoblast ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem

Use of Hyperosmolar Stress to Measure Stress-Activated Protein Kinase Activation and Function in Human HTR Cells and Mouse Trophoblast Stem Cells

2007 ◽  
Vol 14 (6) ◽  
pp. 534-547 ◽  
Author(s):  
Wenjing Zhong ◽  
Yufen Xie ◽  
Yingchun Wang ◽  
Jennifer Lewis ◽  
Anna Trostinskaia ◽  
...  
Keyword(s):  
Stem Cells ◽  
Protein Kinase ◽  
Kinase Activation ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Protein Kinase Activation ◽  
And Function

scholarly journals Histone demethylase JMJD2B/KDM4B regulates transcriptional program via distinctive epigenetic targets and protein interactors for the maintenance of trophoblast stem cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kylie Hin-Man Mak ◽  
Yuk Man Lam ◽  
Ray Kit Ng
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Cell Fate ◽  
Histone Demethylase ◽  
Gene Promoters ◽  
Transcriptional Program ◽  
Binding Motifs ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Trophoblast Stem Cell

AbstractTrophoblast stem cell (TSC) is crucial to the formation of placenta in mammals. Histone demethylase JMJD2 (also known as KDM4) family proteins have been previously shown to support self-renewal and differentiation of stem cells. However, their roles in the context of the trophoblast lineage remain unclear. Here, we find that knockdown of Jmjd2b resulted in differentiation of TSCs, suggesting an indispensable role of JMJD2B/KDM4B in maintaining the stemness. Through the integration of transcriptome and ChIP-seq profiling data, we show that JMJD2B is associated with a loss of H3K36me3 in a subset of embryonic lineage genes which are marked by H3K9me3 for stable repression. By characterizing the JMJD2B binding motifs and other transcription factor binding datasets, we discover that JMJD2B forms a protein complex with AP-2 family transcription factor TFAP2C and histone demethylase LSD1. The JMJD2B–TFAP2C–LSD1 complex predominantly occupies active gene promoters, whereas the TFAP2C–LSD1 complex is located at putative enhancers, suggesting that these proteins mediate enhancer–promoter interaction for gene regulation. We conclude that JMJD2B is vital to the TSC transcriptional program and safeguards the trophoblast cell fate via distinctive protein interactors and epigenetic targets.

scholarly journals From blastocyst to gastrula: gene regulatory networks of embryonic stem cells and early mouse embryogenesis

2014 ◽  
Vol 369 (1657) ◽  
pp. 20130542 ◽  
Author(s):  
David-Emlyn Parfitt ◽  
Michael M. Shen
Keyword(s):  
Stem Cells ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Network Models ◽  
Cell Types ◽  
Mammalian Development ◽  
A Genome

To date, many regulatory genes and signalling events coordinating mammalian development from blastocyst to gastrulation stages have been identified by mutational analyses and reverse-genetic approaches, typically on a gene-by-gene basis. More recent studies have applied bioinformatic approaches to generate regulatory network models of gene interactions on a genome-wide scale. Such models have provided insights into the gene networks regulating pluripotency in embryonic and epiblast stem cells, as well as cell-lineage determination in vivo . Here, we review how regulatory networks constructed for different stem cell types relate to corresponding networks in vivo and provide insights into understanding the molecular regulation of the blastocyst–gastrula transition.

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