Atypical E2F Repressors and Activators Coordinate Placental Development

Ouseph, Madhu M.; Li, Jing; Chen, Hui Zi; Pécot, Thierry; Wenzel, Pamela L.; Thompson, J.; Comstock, Grant; Chokshi, Veda; Byrne, Morgan; Forde, Braxton; Chong, Jean Leon; Huang, Kun; Machiraju, Raghu; Bruin, Alain de; Leone, Gustavo

doi:10.1016/j.devcel.2012.01.013

Cited by 98 publications

(91 citation statements)

References 55 publications

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“…A senescent phenotype of the syncytiotrophoblast, including high DCR2 expression, might contribute to this inactivation and thus support the viability of these cells. Of note, knockout of genes that can regulate senescence (pRb or E2F7) leads to disorganization of the trophoblast in mice and even causes embryonic lethality (Narita et al 2003;Wu et al 2003;Aksoy et al 2012;Ouseph et al 2012). Placenta-specific ablation of pRb, for example, causes embryonic lethality, and placenta malfunction is the defect responsible for the embryonic lethality of pRb knockout mice (Wu et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Cell fusion induced by ERVWE1 or measles virus causes cellular senescence

et al. 2013

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Cellular senescence limits proliferation of potentially detrimental cells, preventing tumorigenesis and restricting tissue damage. However, the function of senescence in nonpathological conditions is unknown. We found that the human placental syncytiotrophoblast exhibited the phenotype and expressed molecular markers of cellular senescence. During embryonic development, ERVWE1-mediated cell fusion results in formation of the syncytiotrophoblast, which serves as the maternal/fetal interface at the placenta. Expression of ERVWE1 caused cell fusion in normal and cancer cells, leading to formation of hyperploid syncytia exhibiting features of cellular senescence. Infection by the measles virus, which leads to cell fusion, also induced cellular senescence in normal and cancer cells. The fused cells activated the main molecular pathways of senescence, the p53-and p16-pRbdependent pathways; the senescence-associated secretory phenotype; and immune surveillance-related proteins. Thus, fusion-induced senescence might be needed for proper syncytiotrophoblast function during embryonic development, and reuse of this senescence program later in life protects against pathological expression of endogenous fusogens and fusogenic viral infections.

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Section: Discussionmentioning

confidence: 99%

Cell fusion induced by ERVWE1 or measles virus causes cellular senescence

et al. 2013

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“…The result indicated negative regulatory elements in the region from g.K1564 to g.K586. Several inhibitory transcription element-binding sites, such as E2F and AML1a, which inhibit the transcriptional activity of genes (Uchida et al 1997, Ousephe et al 2012, were found using the TFSEARCH Online Software (http://www.cbrc.jp/research/db/TFSEARCH.html) in the region from g.K1066 to g.K586. To shorten the core promoter region, we divided the region from g.K699 to g.C130 into three fragments and cloned them into the pGL3-basic luciferase vector.…”

Section: Cloning and Activity Analysis Of Spef2 Promotermentioning

confidence: 99%

Alternative splicing, promoter methylation, and functional SNPs of sperm flagella 2 gene in testis and mature spermatozoa of Holstein bulls

Guo¹,

Yang²,

Ju³

et al. 2014

Reproduction

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The sperm flagella 2 (SPEF2) gene is essential for development of normal sperm tail and male fertility. In this study, we characterized first the splice variants, promoter and its methylation, and functional single-nucleotide polymorphisms (SNPs) of the SPEF2 gene in newborn and adult Holstein bulls. Four splice variants were identified in the testes, epididymis, sperm, heart, spleen, lungs, kidneys, and liver tissues through RT-PCR, clone sequencing, and western blot analysis. Immunohistochemistry revealed that the SPEF2 was specifically expressed in the primary spermatocytes, elongated spermatids, and round spermatids in the testes and epididymis. SPEF2-SV1 was differentially expressed in the sperms of high-performance and low-performance adult bulls; SPEF2-SV2 presents the highest expression in testis and epididymis; SPEF2-SV3 was only detected in testis and epididymis. An SNP (c.2851GOT) in exon 20 of SPEF2, located within a putative exonic splice enhancer, potentially produced SPEF2-SV3 and was involved in semen deformity rate and post-thaw cryopreserved sperm motility. The luciferase reporter and bisulfite sequencing analysis suggested that the methylation pattern of the core promoter did not significantly differ between the full-sib bulls that presented hypomethylation in the ejaculated semen and testis. This finding indicates that sperm quality is unrelated to SPEF2 methylation pattern. Our data suggest that alternative splicing, rather than methylation, is involved in the regulation of SPEF2 expression in the testes and sperm and is one of the determinants of sperm motility during bull spermatogenesis. The exonic SNP (c.2851GOT) produces aberrant splice variants, which can be used as a candidate marker for semen traits selection breeding of Holstein bulls.

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“…Surprisingly, ablation of individual E2Fs in mice has little consequence for cell proliferation and animal development (7). However, the combined ablation of E2F1-3 or E2F7/8 leads to profound alterations in E2F target expression, severely compromising placental, fetal, and postnatal liver development (11)(12)(13)(14), suggesting redundancy within specific E2F subcategories. Importantly, the simultaneous ablation of a single activator (E2F3A in placenta and E2F1 in liver) normalized gene expression and significantly ameliorated developmental phenotypes associated with loss of E2F7/8 atypical repressors (13,14).…”

Section: Introductionmentioning

confidence: 99%

“…However, the combined ablation of E2F1-3 or E2F7/8 leads to profound alterations in E2F target expression, severely compromising placental, fetal, and postnatal liver development (11)(12)(13)(14), suggesting redundancy within specific E2F subcategories. Importantly, the simultaneous ablation of a single activator (E2F3A in placenta and E2F1 in liver) normalized gene expression and significantly ameliorated developmental phenotypes associated with loss of E2F7/8 atypical repressors (13,14). These observations suggest that E2F activators and atypical repressors work in opposition to carefully regulate gene expression and promote the timely transition of cells through the cell cycle, which are necessary to maintain proper hepatocyte ploidy in vivo.…”

Section: Introductionmentioning

confidence: 99%