Epigenetic reshaping through damage: promoting cell fate transition by BrdU and IdU incorporation.

BACKGROUND: Thymidine analogs have long been recognized for their ability to randomly incorporate into DNA. However, the precise mechanisms through which thymidine analogs facilitate cell fate transition remains unclear. RESULTS: Here, we discovered a strong correlation between the dosage dependence of thymidine analogs and their ability to overcome reprogramming barrier. The extraembryonic endoderm (XEN) state seems to be a cell's selective response to DNA damage repair (DDR), offering a shortcut to overcome reprogramming barriers. Meanwhile, we found that homologous recombination repair (HRR) pathway causes an overall epigenetic reshaping of cells and enabling them to overcome greater barriers. This response leads to the creation of a hypomethylated environment, which facilitates the transition of cell fate in various reprogramming systems. We term this mechanism as Epigenetic Reshaping through Damage (ERD). CONCLUSION: Overall, our study finds that BrdU/IdU can activate the DNA damage repair pathway (HRR), leading to increased histone acetylation and genome-wide DNA demethylation, regulating somatic cell reprogramming. This offers valuable insights into mechanisms underlying cell fate transition.

Identifying a novel IRF3/circUHRF1/miR-1306-5p/ARL4C axis in pancreatic ductal adenocarcinoma progression.

Pancreatic ductal adenocarcinoma (PDAC) is considered one most aggressive and lethal cancer types worldwide. While its underlying mechanisms are still poorly understood. CircRNAs play essential roles in various biological progression, including PDAC. Here, our results found that circUHRF1 was highly expressed in PDAC tumor tissues compared with normal tissues. Next, Cell or animal models were constructed, CCK-8, cell colony, EdU, flow cytometry assay, transwell migration, and Western blot assays were applied. CircUHRF1 knockdown influenced PDAC cell proliferation, apoptosis, migration and EMT level in vitro, and tumor growth in vivo. Subsequently, bioinformatics analysis, AGO2-RIP, RNA pull-down, and dual-luciferase reporter assays were used to explore the downstream targets in PDAC progression. Our findings suggest that circUHRF1 regulated ARL4C expression to promote PDAC progression through sponging miR-1306-5p. The role of miR-1306-5p in PDAC cellular progression has been elucidated, and the expression association between miR-1306-5p and circUHRF1 or ARL4C in PDAC tissues was analyzed. Furthermore, circUHRF1 expression in PDAC cells could be transcriptionally regulated by IRF3. Collectively, our study demonstrated the role of IRF3/circUHRF1/miR-1306-5p/ARL4C axis in PDAC progression. Our results suggest that circUHRF1 is one promising diagnosis or therapeutic target for PDAC management.Abbreviations : CircRNA; Circular RNAPDAC; pancreatic ductal adenocarcinomaUHRF1; Ubiquitin-like with PHD and RING finger domain 1ARL4C; ADP Ribosylation Factor Like GTPase 4CRIP; RNA immunoprecipitationEDU; 5-Ethynyl-2'-deoxyuridineEMT; epithelial to mesenchymal transitionAGO2; Argonaute RISC Catalytic Component 2CCK8; Cell counting Kit-8IRF3; Interferon Regulatory Factor 3.

MK2 promotes Tfcp2l1 degradation via ß-TrCP ubiquitin ligase to regulate mouse embryonic stem cell self-renewal.

Tfcp2l1 can maintain mouse embryonic stem cell (mESC) self-renewal. However, it remains unknown how Tfcp2l1 protein stability is regulated. Here, we demonstrate that ß-transducin repeat-containing protein (ß-TrCP) targets Tfcp2l1 for ubiquitination and degradation in a mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2)-dependent manner. Specifically, ß-TrCP1 and ß-TrCP2 recognize and ubiquitylate Tfcp2l1 through the canonical ß-TrCP-binding motif DSGDNS, in which the serine residues have been phosphorylated by MK2. Point mutation of serine-to-alanine residues reduces ß-TrCP-mediated ubiquitylation and enhances the ability of Tfcp2l1 to promote mESC self-renewal while repressing the speciation of the endoderm, mesoderm, and trophectoderm. Similarly, inhibition of MK2 reduces the association of Tfcp2l1 with ß-TrCP1 and increases the self-renewal-promoting effects of Tfcp2l1, whereas overexpression of MK2 or ß-TrCP genes decreases Tfcp2l1 protein levels and induces mESC differentiation. Collectively, our study reveals a posttranslational modification of Tfcp2l1 that will expand our understanding of the regulatory network of stem cell pluripotency.

Long noncoding RNA NEAT1 promotes progression of glioma as a ceRNA by sponging miR-185-5p to stimulate DNMT1/mTOR signaling.

Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) is regarded as an oncogene in multiple cancers. Previous studies have shown that NEAT1 is involved in the proliferation and tumorigenesis of glioma cells, while miR-185-5p functions as a tumor suppressor in glioma. However, the underlying molecular mechanism of NEAT1 in glioma, especially in association with miR-185-5p, has not been studied. In this study, we first demonstrated that NEAT1 expression was upregulated, and miR-185-5p downregulated in glioma tissues and cells. More important, NEAT1 expression was negatively correlated with miR-185-5p expression in glioma tissues. In vitro and in vivo experiments verified that NEAT1 was a competing endogenous RNA for miR-185-5p for promoting DNA methyltransferase 1 (DNMT1) expression and activated mammalian target of rapamycin (mTOR) signaling, thus inhibiting apoptosis, and promoting glioma migration, proliferation, and epithelial-mesenchymal transition process. Furthermore, NEAT1 knockdown suppressed tumor growth and reduced the expression of proliferation antigen Ki-67, DNMT1, and mTOR, but upregulated the expression of miR-185-5p in vivo. Finally, with mTOR inhibitor rapamycin, we confirmed that NEAT1 promoted glioma activity through mTOR signaling both in vitro and in vivo. In conclusion, these results suggest that NEAT1 promotes glioma tumorigenesis via miR-185-5p/DNMT1/mTOR signaling, which may provide a new target for the diagnosis and therapy of glioma.

Down-regulation of circ_0061140 attenuates ectopic endometrial cell proliferation, migration and invasion in endometriosis via inactivating Notch2.

Endometriosis is a frequent gynecologic disease in the world. CircRNAs can exert a crucial role in various diseases. Nevertheless, little is known about its roles in endometriosis. We investigated the involvement of circ_0061140 in endometriosis. Tissues from endometriosis women displayed an increased expression of circ_0061140. Then, we found loss of circ_0061140 significantly repressed ectopic endometrial cell proliferation, migration and invasion. Meanwhile,miR-140-3pcan demonstrate an important role in several cancers.Here, we reported miR-140-3p was reduced in ectopic endometrial cells and it acted as a target of circ_0061140. Moreover, miR-140-3p was able to reverse the effect of circ_0061140 on ectopic endometrial cells. Furthermore, Notch2 was predicted as a putative target of miR-140-3p. A positive correlation between circ_0061140 and Notch2 was indicated. miR-140-3p and Notch2 were operated as downstream effectors in the circ_0061140 mediated signaling in endometriosis. Decrease of circ_0061140 could depress endometriosis progression through modulating miR-140-3p and Notch2.