scholarly journals ZFP57 dictates allelic expression switch of target imprinted genes

2021 ◽  
Vol 118 (5) ◽  
pp. e2005377118
Author(s):  
Weijun Jiang ◽  
Jiajia Shi ◽  
Jingjie Zhao ◽  
Qiu Wang ◽  
Dan Cong ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Notch Signaling ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Mouse Embryos ◽  
The Other ◽  
Allelic Expression ◽  
Monoallelic Expression ◽  
Imprinted Genes ◽  
Parent Of Origin

ZFP57 is a master regulator of genomic imprinting. It has both maternal and zygotic functions that are partially redundant in maintaining DNA methylation at some imprinting control regions (ICRs). In this study, we found that DNA methylation was lost at most known ICRs in Zfp57 mutant embryos. Furthermore, loss of ZFP57 caused loss of parent-of-origin–dependent monoallelic expression of the target imprinted genes. The allelic expression switch occurred in the ZFP57 target imprinted genes upon loss of differential DNA methylation at the ICRs in Zfp57 mutant embryos. Specifically, upon loss of ZFP57, the alleles of the imprinted genes located on the same chromosome with the originally methylated ICR switched their expression to mimic their counterparts on the other chromosome with unmethylated ICR. Consistent with our previous study, ZFP57 could regulate the NOTCH signaling pathway in mouse embryos by impacting allelic expression of a few regulators in the NOTCH pathway. In addition, the imprinted Dlk1 gene that has been implicated in the NOTCH pathway was significantly down-regulated in Zfp57 mutant embryos. Our allelic expression switch models apply to the examined target imprinted genes controlled by either maternally or paternally methylated ICRs. Our results support the view that ZFP57 controls imprinted expression of its target imprinted genes primarily through maintaining differential DNA methylation at the ICRs.

scholarly journals The influence of DNA methylation on monoallelic expression

2019 ◽  
Vol 63 (6) ◽  
pp. 663-676 ◽  
Author(s):  
Simão Teixeira da Rocha ◽  
Anne-Valerie Gendrel
Keyword(s):  
Dna Methylation ◽  
Expression Patterns ◽  
Monoallelic Expression ◽  
Imprinted Genes ◽  
Dependent Manner ◽  
Epigenetic Mechanisms ◽  
Cpg Sites ◽  
Mammalian Genomes ◽  
Parent Of Origin ◽  
Diploid Cells

Abstract Monoallelic gene expression occurs in diploid cells when only one of the two alleles of a gene is active. There are three main classes of genes that display monoallelic expression in mammalian genomes: (1) imprinted genes that are monoallelically expressed in a parent-of-origin dependent manner; (2) X-linked genes that undergo random X-chromosome inactivation in female cells; (3) random monoallelically expressed single and clustered genes located on autosomes. The heritability of monoallelic expression patterns during cell divisions implies that epigenetic mechanisms are involved in the cellular memory of these expression states. Among these, methylation of CpG sites on DNA is one of the best described modification to explain somatic inheritance. Here, we discuss the relevance of DNA methylation for the establishment and maintenance of monoallelic expression patterns among these three groups of genes, and how this is intrinsically linked to development and cellular states.

scholarly journals Notch receptors as a therapeutic target in melanoma: a narrative bibliographic review

2021 ◽  
Vol 4 (1) ◽  
pp. 614-628
Author(s):  
Renato Santos de Oliveira Filho ◽  
Guilherme Routh Peixoto ◽  
Lorena Dal Collina Sangiuliano ◽  
Daniel Arcuschin de Oliveira
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Cutaneous Melanoma ◽  
Target Therapy ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Narrative Review ◽  
The Other ◽  
Cochrane Library ◽  
Targeting Therapy

Melanoma is the skin cancer with higher mortality and more and more cases are arising every year. Overexpression of Notch signaling pathway elements have already been found in primary and metastatic melanoma lineages, and directly correlated to melanoma’s development, growth, angiogenesis, metastasis, and resistance to treatment. Thus, target therapy against Notch in melanoma presents a high potential for the treatment of this type of cancer.        In this review we aim to perform a narrative review on melanoma’s possible treatments targeting the Notch pathway. We searched literature about Notch signaling pathway inhibitors in human cutaneous melanoma published between 2000 and 2020 using MEDLINE (via PubMed), LILACS (via Biblioteca Virtual em Saúde) and Cochrane Library databases. The selected articles were analyzed, summarized, tabulated, and used to produce the present narrative review. The 24 selected articles, as well as articles referenced in them, presented as targeting therapy against Notch, γ-secretase inhibitors (GSIs), primarily, but also gliotoxin, honokiol, phospholipase A2, andrographolide and monoclonal antibodies, that, however, were not directly studied in melanoma. Another therapy that indirectly interfered in the Notch signaling pathway and was found in these articles were G9a inhibitors. Analyzing the collected data, it was possible to conclude that GSIs, more extensively studied, are probably not the best option for melanoma’s treatment, exceeding specific scenarios or through their concomitant use with other pathways inhibitors. The use of the other compounds, on the other hand, has greater potential, however, more studies are needed to prove its effectiveness and viability for the treatment of human cutaneous melanoma.  

Hairy/E(spl)-related(Her) genes are central components of the segmentation oscillator and display redundancy with the Delta/Notch signaling pathway in the formation of anterior segmental boundaries in the zebrafish

Development ◽  
2002 ◽  
Vol 129 (12) ◽  
pp. 2929-2946 ◽  
Author(s):  
Andrew C. Oates ◽  
Robert K. Ho
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Central Component ◽  
Mutant Genotype ◽  
Her Family ◽  
Somite Formation ◽  
Anterior Segments ◽  
Her Genes

We have examined the expression of a Hairy/E(spl)-related (Her) gene, her7, in the zebrafish and show that its expression in the PSM cycles similarly to her1 and deltaC. A decrease in her7 function generated by antisense oligonucleotides disrupts somite formation in the posterior trunk and tail, and disrupts the dynamic expression domains of her1 and deltaC, suggesting that her7 plays a role in coordinating the oscillations of neighboring cells in the presomitic mesoderm. This phenotype is reminiscent of zebrafish segmentation mutants with lesions in genes of the Delta/Notch signaling pathway, which also show a disruption of cyclic her7 expression. The interaction of HER genes with the Delta/Notch signaling system was investigated by introducing a loss of her7 function into mutant backgrounds. This leads to segmental defects more anterior than in either condition alone. Combining a decrease of her7 function with reduction of her1 function results in an enhanced phenotype that affects all the anterior segments, indicating that Her functions in the anterior segments are also partially redundant. In these animals, gene expression does not cycle at any time, suggesting that a complete loss of oscillator function had been achieved. Consistent with this, combining a reduction of her7 and her1 function with a Delta/Notch mutant genotype does not worsen the phenotype further. Thus, our results identify members of the Her family of transcription factors that together behave as a central component of the oscillator, and not as an output. This indicates, therefore, that the function of the segmentation oscillator is restricted to the positioning of segmental boundaries. Furthermore, our data suggest that redundancy between Her genes and genes of the Delta/Notch pathway is in part responsible for the robust formation of anterior somites in vertebrates.

The Notch signalling pathway and breast cancer: The importance of balance and cellular self-control.

2019 ◽  
Vol 14 ◽  
Author(s):  
Germán Saucedo-Correa ◽  
Alejandro Bravo-Patiño ◽  
Rosa Elvira Núñez-Anita ◽  
Javier Oviedo-Boyso ◽  
Juan José Valdez-Alarcón ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Cross Talk ◽  
Transcriptional Activation ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Self Control ◽  
Design Strategies ◽  
Notch Intracellular Domain ◽  
The Cross

Notch is a cell-signaling pathway that is highly conserved in all metazoans and is responsible for cell differentiation and cross-talk communication with other signaling pathways such as WNT and Hh. In most cancers, the Notch signaling pathway is altered, causing atypical activity of vital processes such as cell cycle, differentiation and apoptosis, leading the cell to a carcinogenic state. Currently, the Notch signaling pathway has taken a special interest to design strategies in order to regulate the activity of this pathway since it is known that in the cancer molecular micro-environment the Notch pathway is over-expressed or presents an aberrant function, which, in consequence, corrupts the cross-talk communication with WNT and Hh pathways. Most of the existing strategies are focused on the systematic and whole inhibition of Notch pathway at the membrane level by the use of γ-secretases inhibitors. There are few strategies that act at the nuclear level inhibiting the activity of the transcriptional activation complex composed by the Notch intracellular domain, the transcriptional factor CSL and the Mastermind co-activator. In this review, by the fact that there are not any strategy focused to revert the over expression effect caused by the Notch pathway constitutive activity, we propose that the efforts to develop new strategies against cancer should be focused to understand the complexity of the cross-talk communication between Notch, WNT and Hh pathways to neutralize the gene aberrant activity characteristic of cancer cells which are responsible for those corrupted cross-talk communication.

Imprinting analysis in the Acrodysplasia region of mouse chromosome 12

2009 ◽  
Vol 30 (2) ◽  
pp. 119-124 ◽  
Author(s):  
Erin N. McMurray ◽  
Eric D. Rogers ◽  
Jennifer V. Schmidt
Keyword(s):  
Mouse Chromosome ◽  
Genomic Imprinting ◽  
Critical Region ◽  
The Other ◽  
Chromosome 12 ◽  
Imprinted Genes ◽  
Skeletal Abnormalities ◽  
Mouse Mutation ◽  
Parent Of Origin

The insertional mouse mutation Adp (Acrodysplasia) confers a parent-of-origin developmental phenotype, with animals inheriting the mutation from their father showing skeletal abnormalities, whereas those inheriting the mutation from their mother are normal. This parental-specific phenotype, along with mapping of the insertion to a region of chromosome 12 proposed to contain imprinted genes, suggested that disruption of genomic imprinting might underlie the Adp phenotype. Genomic imprinting is the process by which autosomal genes are epigenetically silenced on one of the two parental alleles; imprinting mutation phenotypes manifest after inheritance from one parent but not the other. Imprinted genes typically occur in dense clusters that contain few non-imprinted genes and therefore representative genes from the Adp critical region could be assayed to identify any imprinted domains. None of the genes analysed were found to be imprinted, however, suggesting that other explanations for the Adp phenotype must be considered.

scholarly journals Suppression of Notch Signaling Stimulates Progesterone Synthesis by Enhancing the Expression of NR5A2 and NR2F2 in Porcine Granulosa Cells

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 120
Author(s):  
Rihong Guo ◽  
Fang Chen ◽  
Zhendan Shi
Keyword(s):  
Notch Signaling ◽  
Granulosa Cells ◽  
Butyl Ester ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Progesterone Secretion ◽  
Expression Of Genes ◽  
Porcine Granulosa Cells ◽  
Progesterone Synthesis ◽  
Progesterone Biosynthesis

The conserved Notch pathway is reported to be involved in progesterone synthesis and secretion; however, the exact effects remain controversial. To determine the role and potential mechanisms of the Notch signaling pathway in progesterone biosynthesis in porcine granulosa cells (pGCs), we first used a pharmacological γ-secretase inhibitor, N-(N-(3,5-difluorophenacetyl-l-alanyl))-S-phenylglycine t-butyl ester (DAPT), to block the Notch pathway in cultured pGCs and then evaluated the expression of genes in the progesterone biosynthesis pathway and key transcription factors (TFs) regulating steroidogenesis. We found that DAPT dose- and time-dependently increased progesterone secretion. The expression of steroidogenic proteins NPC1 and StAR and two TFs, NR5A2 and NR2F2, was significantly upregulated, while the expression of HSD3B was significantly downregulated. Furthermore, knockdown of both NR5A2 and NR2F2 with specific siRNAs blocked the upregulatory effects of DAPT on progesterone secretion and reversed the effects of DAPT on the expression of NPC1, StAR, and HSD3B. Moreover, knockdown of NR5A2 and NR2F2 stimulated the expression of Notch3. In conclusion, the inhibition of Notch signaling stimulated progesterone secretion by enhancing the expression of NPC1 and StAR, and the two TFs NR5A2 and NR2F2 acted as downstream TFs of Notch signaling in regulating progesterone synthesis.

scholarly journals Evolution of imprinting via lineage-specific insertion of retroviral promoters

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Aaron B. Bogutz ◽  
Julie Brind’Amour ◽  
Hisato Kobayashi ◽  
Kristoffer N. Jensen ◽  
Kazuhiko Nakabayashi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Endogenous Retroviruses ◽  
The Other ◽  
Imprinted Genes ◽  
Evolutionary Mechanism ◽  
Female Mice ◽  
Parental Allele ◽  
Species Specific ◽  
Human Specific

AbstractImprinted genes are expressed from a single parental allele, with the other allele often silenced by DNA methylation (DNAme) established in the germline. While species-specific imprinted orthologues have been documented, the molecular mechanisms underlying the evolutionary switch from biallelic to imprinted expression are unknown. During mouse oogenesis, gametic differentially methylated regions (gDMRs) acquire DNAme in a transcription-guided manner. Here we show that oocyte transcription initiating in lineage-specific endogenous retroviruses (ERVs) is likely responsible for DNAme establishment at 4/6 mouse-specific and 17/110 human-specific imprinted gDMRs. The latter are divided into Catarrhini- or Hominoidea-specific gDMRs embedded within transcripts initiating in ERVs specific to these primate lineages. Strikingly, imprinting of the maternally methylated genes Impact and Slc38a4 was lost in the offspring of female mice harboring deletions of the relevant murine-specific ERVs upstream of these genes. Our work reveals an evolutionary mechanism whereby maternally silenced genes arise from biallelically expressed progenitors.

scholarly journals Cancer Stem Cells, Quo Vadis? The Notch Signaling Pathway in Tumor Initiation and Progression

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1879 ◽  
Author(s):  
Christian T. Meisel ◽  
Cristina Porcheri ◽  
Thimios A. Mitsiadis
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Cell Fate ◽  
Adult Life ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Fine Tuning ◽  
Cell Fate Decisions

The Notch signaling pathway regulates cell proliferation, cytodifferentiation and cell fate decisions in both embryonic and adult life. Several aspects of stem cell maintenance are dependent from the functionality and fine tuning of the Notch pathway. In cancer, Notch is specifically involved in preserving self-renewal and amplification of cancer stem cells, supporting the formation, spread and recurrence of the tumor. As the function of Notch signaling is context dependent, we here provide an overview of its activity in a variety of tumors, focusing mostly on its role in the maintenance of the undifferentiated subset of cancer cells. Finally, we analyze the potential of molecules of the Notch pathway as diagnostic and therapeutic tools against the various cancers.

Association between Notch signaling pathway and cancer

2013 ◽  
Vol 19 (4) ◽  
pp. 427-437
Author(s):  
Nadežda Lachej ◽  
Janina Didžiapetrienė ◽  
Birutė Kazbarienė ◽  
Daiva Kanopienė ◽  
Violeta Jonušienė
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Pathway ◽  
Treatment Method ◽  
Notch Signaling Pathway ◽  
Published Data ◽  
Undifferentiated Cells ◽  
Oncologic Diseases ◽  
Worse Prognosis

Background. The components of the Notch signaling pathway are important in maintaining the balance involved in cell proliferation, apoptosis and differentiation. Therefore, dysfunction of the Notch prevents differentiation, ultimately guiding undifferentiated cells toward malignant transformation. The aim of this article is to present recently published data concerning the role of the Notch signaling pathway components in development and prognosis of oncologic diseases, in occurrence of resistance to cytostatic agents and importance in creating of new cancer treatment approaches. Materials and methods. The Pubmed was the main source of looking for information for this article. Results. Recent investigations show that disorders of the Notch signaling pathway are associated with development of some human haematological and solid cancers. In different tissues and organs this active pathway can act as a tumor suppressor or an oncogene. Accordingly, the increased or decreased expression of its components is defined. Most of published data show that the increased expression of Notch pathway components correlates with a worse prognosis of cancer and a shorter survival. Recently, the Notch pathway has been reported to be involved in drug resistance. The modulation of the Notch signaling pathway could be helpful in treatment of some tumors with abnormal activity of this pathway’s components. Therefore changes in the expression of Notch components could become important predictive factors, helpful in selecting the proper treatment method. Conclusions. The results of recent studies are very important, since the detecting of the prognostic and predictive value of components of the Notch signaling pathway can allow creating new and improving already known methods of cancer diagnostic and treatment.

Expression of Notch signaling pathway genes in mouse embryos lacking β4galactosyltransferase-1

2006 ◽  
Vol 6 (4) ◽  
pp. 376-382 ◽  
Author(s):  
Jihua Chen ◽  
Linchao Lu ◽  
Shaolin Shi ◽  
Pamela Stanley
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Signaling Pathway ◽  
Mouse Embryos
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