scholarly journals Genome Modifications Involved in Developmental Programs of the Placental Trophoblast

2021 ◽  
Author(s):  
Tatiana G. Zybina
Keyword(s):  
Cell Differentiation ◽  
Gene Copy Number ◽  
Histone Variants ◽  
Mitotic Division ◽  
Trophoblast Cell ◽  
Extravillous Trophoblast ◽  
Gene Copy ◽  
Trophoblast Cells ◽  
Genome Modifications

The placental trophoblast cells give an example of profound genome modifications that lead to whole-genome multiplication, aneuploidy, under-replication of some genes or their clusters as well as, by contrast, gene amplification. These events are included into program of differentiation of functionally different cell lineages. In some cases the trophoblast cell differentiation involves depolyploidization achieved by non-mitotic division. Aneuploidy may be also accounted for by the unusual mitoses characteristic of Invertebrates and plants; in mammalian it may result from hypomethylation of centromere chromosome regions. The giant (endopolyploid) trophoblast cells organization includes “loose nucleosomes” accounted for by the non-canonical histone variants, i.e. H2AX, H2AZ, and H3. 3 . In the human extravillous trophoblast cells that, like murine TGC, invade endometrium, there occured significant changes of methylation as compared to non-invasive trophoblast cell populations . Meantime, some genes show hypermethylation connected with start of trophoblast lineages specification. Thus, despite the limited possibilities of chromosome visualization trophoblast cells represent an interesting model to investigate the role of modification of gene copy number and their expression that is important for the normal or abnormal cell differentiation.

Intersection of regulatory pathways controlling hemostasis and hemochorial placentation

2021 ◽  
Vol 118 (50) ◽  
pp. e2111267118
Author(s):  
Masanaga Muto ◽  
Damayanti Chakraborty ◽  
Kaela M. Varberg ◽  
Ayelen Moreno-Irusta ◽  
Khursheed Iqbal ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Differentiation ◽  
Cell Invasion ◽  
Cell Development ◽  
Trophoblast Cell ◽  
Extravillous Trophoblast ◽  
Cell Phenotype ◽  
Trophoblast Cells ◽  
Rat Models ◽  
Endovascular Trophoblast

Hemochorial placentation is characterized by the development of trophoblast cells specialized to interact with the uterine vascular bed. We utilized trophoblast stem (TS) cell and mutant rat models to investigate regulatory mechanisms controlling trophoblast cell development. TS cell differentiation was characterized by acquisition of transcript signatures indicative of an endothelial cell-like phenotype, which was highlighted by the expression of anticoagulation factors including tissue factor pathway inhibitor (TFPI). TFPI localized to invasive endovascular trophoblast cells of the rat placentation site. Disruption of TFPI in rat TS cells interfered with development of the endothelial cell-like endovascular trophoblast cell phenotype. Similarly, TFPI was expressed in human invasive/extravillous trophoblast (EVT) cells situated within first-trimester human placental tissues and following differentiation of human TS cells. TFPI was required for human TS cell differentiation to EVT cells. We next investigated the physiological relevance of TFPI at the placentation site. Genome-edited global TFPI loss-of-function rat models revealed critical roles for TFPI in embryonic development, resulting in homogeneous midgestation lethality prohibiting analysis of the role of TFPI as a regulator of the late-gestation wave of intrauterine trophoblast cell invasion. In vivo trophoblast-specific TFPI knockdown was compatible with pregnancy but had profound effects at the uterine–placental interface, including restriction of the depth of intrauterine trophoblast cell invasion while leading to the accumulation of natural killer cells and increased fibrin deposition. Collectively, the experimentation implicates TFPI as a conserved regulator of invasive/EVT cell development, uterine spiral artery remodeling, and hemostasis at the maternal–fetal interface.

scholarly journals ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development

2021 ◽  
Vol 118 (10) ◽  
pp. e2016517118
Author(s):  
Kaela M. Varberg ◽  
Khursheed Iqbal ◽  
Masanaga Muto ◽  
Mikaela E. Simon ◽  
Regan L. Scott ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Invasion ◽  
Cell Lineage ◽  
Trophoblast Cell ◽  
Extravillous Trophoblast ◽  
Sequencing Analysis ◽  
Spiral Artery ◽  
Trophoblast Cells ◽  
Junctional Zone ◽  
Artery Remodeling

Invasive trophoblast cells are critical to spiral artery remodeling in hemochorial placentation. Insufficient trophoblast cell invasion and vascular remodeling can lead to pregnancy disorders including preeclampsia, preterm birth, and intrauterine growth restriction. Previous studies in mice identified achaete-scute homolog 2 (ASCL2) as essential to extraembryonic development. We hypothesized that ASCL2 is a critical and conserved regulator of invasive trophoblast cell lineage development. In contrast to the mouse, the rat possesses deep intrauterine trophoblast cell invasion and spiral artery remodeling similar to human placentation. In this study, we investigated invasive/extravillous trophoblast (EVT) cell differentiation using human trophoblast stem (TS) cells and a loss-of-function mutant Ascl2 rat model. ASCL2 transcripts are expressed in the EVT column and junctional zone, which represent tissue sources of invasive trophoblast progenitor cells within human and rat placentation sites, respectively. Differentiation of human TS cells into EVT cells resulted in significant up-regulation of ASCL2 and several other transcripts indicative of EVT cell differentiation. Disruption of ASCL2 impaired EVT cell differentiation, as indicated by cell morphology and transcript profiles. RNA sequencing analysis of ASCL2-deficient trophoblast cells identified both down-regulation of EVT cell-associated transcripts and up-regulation of syncytiotrophoblast-associated transcripts, indicative of dual activating and repressing functions. ASCL2 deficiency in the rat impacted placental morphogenesis, resulting in junctional zone dysgenesis and failed intrauterine trophoblast cell invasion. ASCL2 acts as a critical and conserved regulator of invasive trophoblast cell lineage development and a modulator of the syncytiotrophoblast lineage.

scholarly journals Downregulation of LncRNA-MEG3 promotes HTR8/SVneo cells apoptosis and attenuates its migration by repressing Notch1 signal in preeclampsia

Reproduction ◽  
2020 ◽  
Vol 160 (1) ◽  
pp. 21-29
Author(s):  
Rongli Wang ◽  
Li Zou
Keyword(s):  
Cell Migration ◽  
Cell Apoptosis ◽  
Noncoding Rna ◽  
Cell Function ◽  
Trophoblast Cell ◽  
Extravillous Trophoblast ◽  
Biological Behavior ◽  
Migration And Invasion ◽  
Trophoblast Cells

A successful pregnancy crucially depends on well-regulated extravillous trophoblast migration and invasion. Maternally expressed gene 3 (MEG3) is a long noncoding RNA that plays an important role in regulating trophoblast cells cell function. As previously reported, the expression of MEG3 was reduced in preeclampsia, and downregulation of MEG3 could suppress trophoblast cells migration and promote its apoptosis. However, the downstream regulatory mechanism of MEG3 remains unknown. As reported, MEG3 could inhibit cell proliferation in endometrial carcinoma by regulating Notch signaling. Our previous studies have demonstrated that Notch1 is downregulated in preeclampsia and that inhibiting the expression of Notch1 could promote trophoblast cell apoptosis. Therefore, this study was designed to investigate the role of MEG3 and its the relationship with Notch1 in trophoblasts. In this study, the mRNA expression levels of both MEG3 and Notch1 were decreased in preeclampsia placenta (n = 15) compared to the normal samples (n = 15). Exogenous upregulation and downregulation of MEG3 in HTR8/SVneo cells were performed to investigate the role of MEG3 in cell biological behavior and its effects on Notch1 expression. The results showed that MEG3 enhancement promoted trophoblast cell migration and invasion and inhibited cell apoptosis. Downregulation of MEG3 elicited the opposite results. Associated factors, such as matrix metalloproteinases 2 (MMP2), BAX, and Bcl-2, were examined at the mRNA and protein levels. Our study demonstrated that MEG3 could regulate Notch1 expression to modulate trophoblast cell migration, invasion, and apoptosis, which may represent the molecular mechanism of poor placentation during preeclampsia.

The Role of Cell Growth-Related Gene Copy Number Variation in Autoimmune Thyroid Disease

2019 ◽  
Vol 195 (2) ◽  
pp. 409-416 ◽  
Author(s):  
Yunfeng Guan ◽  
Lixiang Liu ◽  
Qingzhen Jia ◽  
Xing Jin ◽  
Yi Pang ◽  
...  
Keyword(s):  
Cell Growth ◽  
Copy Number ◽  
Autoimmune Thyroid Disease ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Related Gene ◽  
Autoimmune Thyroid ◽  
Gene Copy Number Variation ◽  
Number Variation

Frequent LOH of CYP2D6 in ER+ breast cancer determined by next-generation sequencing (NGS).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 534-534
Author(s):  
Mark J. Ratain ◽  
James Sun ◽  
Yusuke Nakamura ◽  
Nancy J Cox ◽  
Tarek Sahmoud ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Sequence Data ◽  
Biological Significance ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Full Cohort ◽  
Next Generation Sequencing Ngs ◽  
Apparent Association

534 Background: The role of CYP2D6 genetic variation in predicting response to tamoxifen in ER+ breast cancer is a subject of ongoing debate. There has been great variability in approaches to both genotyping and phenotyping, and in particular many investigators have extracted DNA from breast cancer samples rather than peripheral blood. We hypothesized that CYP2D6 gene copy number alterations are common in ER+ breast cancer, affecting genotype results, and used NGS to characterize CYP2D6 in patients with ER+ disease. Methods: CYP2D6 sequencing was performed as part of a comprehensive NGS profile of cancer-related genes for 261 predominantly relapsed and metastatic ER+ breast cancer FFPE specimens. Sequence data were resolved into genotypes according to the * allele nomenclature. Tumor LOH was determined at CYP2D6, and its error impact on genotyping methods was estimated. To assess biological significance, the prevalence of CYP2D6 alleles and LOH in ER+ disease was compared against a control set of 99 ER- tumors. Results: CYP2D6 allele frequencies in our full cohort (ER+, 261; ER-, 99) were consistent with prior studies; 64.4%, 16.8%, 9.0% vs. 63.1%, 17.2%, 7.0% for *1/*2, *4, and *41 respectively, and 1%-2% for the rarer alleles *9, *10, and *5. The rate of CYP2D6 LOH was higher in ER+ disease (41% vs. 26%, p<0.01), with all excess arising from copy-loss (as opposed to copy-neutral) changes (22% vs. 7%, p<0.002). The estimated impact of LOH on germline genotype assessment from tumor was considerable; an assay sensitive at >20% minor allele frequency (e.g., Sanger sequencing) can misclassify >10% of heterozygotes, leading to significant Hardy-Weinberg disequilibrium (e.g., p=8.3x10-8 for *4). Interestingly, an enrichment of reduced or non-functional CYP2D6 alleles in ER+ samples was observed (61% vs. 47%, p<0.03). Conclusions: Our results demonstrate the distorting effect of extensive LOH on genotype assessment of CYP2D6 in breast cancer. Therefore, tumor DNA should not be routinely used for determination of germline 2D6 genotype, although it appears possible to use NGS. The apparent association between reduced function CYP2D6 alleles and ER+ breast cancer in our dataset requires further investigation.

Prognostic role of plasma HER2 gene copy number in patients with HER2 positive metastatic breast cancer.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e13018-e13018 ◽  
Author(s):  
Ran Ran ◽  
Wenfa Huang ◽  
Shao Lin ◽  
Yunyun Niu ◽  
Hope S. Rugo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Copy Number ◽  
Gene Copy Number ◽  
Metastatic Breast ◽  
Gene Copy ◽  
Prognostic Role ◽  
Her2 Gene ◽  
Her2 Positive

scholarly journals Pyrite oxidization accelerates bacterial carbon sequestration in copper mine tailings Type of contribution

2018 ◽  
Author(s):  
Yang Li ◽  
Zhaojun Wu ◽  
Xingchen Dong ◽  
Zifu Xu ◽  
Zhongjun Jia ◽  
...  
Keyword(s):  
Carbon Sequestration ◽  
Mine Tailings ◽  
Copy Number ◽  
Isotope Labeling ◽  
Gene Copy Number ◽  
Stable Isotope Probing ◽  
Gene Copy ◽  
Cbbl Gene ◽  
Heavy Fractions

Abstract. Polymetallic mine tailings have great potential as carbon sequestration tools to stabilize atmospheric CO2 concentrations. However, previous studies focused on carbonate mineral precipitation, while the role of autotrophs in carbon sequestration by mine tailings has been neglected. In this study, carbon sequestration in two mine tailings treated with FeS2 and 13C-labeled CO2 was analyzed using 13C isotope labeling, pyrosequencing and DNA-based stable isotope probing (SIP) to identify carbon fixers. Mine tailings treated with FeS2 exhibited a higher percentage of 13C atoms (1.76 ± 0.06 in Yangshanchong and 1.36 ± 0.01 in Shuimuchong) than the control groups over a 14-day incubation, as well an increase in the total organic carbon (TOC) content (0.20 ± 0.11 mg/g in Yangshanchong and 0.28 ± 0.14 mg/g in Shuimuchong). These data demonstrated the role of autotrophs in carbon sequestration with pyrite addition. Pyrite treatment led to changes in the composition of bacterial communities, and the genera Sulfobacillus (8.04 %) and Novosphingobium (8.60 %) were found to be dominant in these communities. In addition, the DNA-SIP results indicated that the cbbL gene copy number was 8.20–16.50 times greater than the cbbL gene copy number in 13C-labeled heavy fractions. Furthermore, a Sulfobacillus-like cbbL gene sequence (cbbL-OTU1) accounted for 30.11–34.74 % of all cbbL gene sequences in the 13C-labeled heavy fractions of mine tailings treated with FeS2. These findings highlight the importance of the RubisCO form I-encoding gene, cbbL, in bacterial carbon sequestration and demonstrate the ability of chemoautotrophs to sequester carbon during sulfide mineral oxidation in mine tailings. This study is the first to investigate carbon sequestration by autotrophic groups in mine tailings through the use of isotope tracers and DNA-SIP.

scholarly journals TERT aberrancies: a screening tool for malignancy in follicular thyroid tumours

2018 ◽  
Vol 25 (7) ◽  
pp. 723-733 ◽  
Author(s):  
Johan O Paulsson ◽  
Ninni Mu ◽  
Ivan Shabo ◽  
Na Wang ◽  
Jan Zedenius ◽  
...  
Keyword(s):  
Screening Tool ◽  
Gene Copy Number ◽  
Promoter Hypermethylation ◽  
Malignant Potential ◽  
Gene Copy ◽  
Clinical Parameters ◽  
Uncertain Malignant Potential ◽  
Increased Risk ◽  
Promoter Mutations

Telomerase reverse transcriptase (TERT) promoter mutations have been linked to adverse clinical parameters in thyroid cancer, butTERT-expressing tumours are not always mutated. Little is known regarding otherTERT-related genetic aberrations. To delineate the role ofTERTgene aberrancies in follicular thyroid tumours, 95 follicular carcinomas (FTCs), 43 follicular adenomas (FTAs) and 33 follicular tumours of uncertain malignant potential (FT-UMPs) were collected. The tumours were assayed forTERTexpression,TERTpromoter mutations,TERTpromoter hypermethylation andTERTgene copy number (CN) alterations and the results were compared to clinical parameters. Cases with mutation, detectable mRNA expression, CN gain or hypermethylation were classified asTERTaberrant, and these aberrancies were regularly found in FTC and FT-UMP but uncommonly found in FTA. In total, 59% FTCs and 63% FT-UMPs exhibited one or more of theseTERTgene aberrancies. Moreover, 24 out of 28 FTCs (86%) withTERTexpression displayed an evidentTERTgene aberration, and statistics showed an increased risk for relapse in FTCs withTERTexpression, CN gain or hypermethylation. We conclude thatTERTexpression in follicular thyroid tumours is coupled to promoter mutations, CN gain and increased promoter methylation. The molecular similarities regardingTERTaberrations between the FTC and FT-UMP groups indicate that a significant subset of FT-UMP cases may display future recurrences.TERTaberrancies are thus promising as future additional markers for determining malignant potential of follicular thyroid tumours.

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