Multiple enhancers co-regulating the same gene is prevalent and plays a crucial role during development and disease. However, how multiple enhancers coordinate the same gene expression across various ...cell types remains largely unexplored at genome scale.
We develop a computational approach that enables the quantitative assessment of enhancer specificity and selectivity across diverse cell types, leveraging enhancer-promoter (E-P) interactions data. We observe two well-known gene regulation patterns controlled by enhancer clusters, which regulate the same gene either in a limited number of cell types (Specific pattern, Spe) or in the majority of cell types (Conserved pattern, Con), both of which are enriched for super-enhancers (SEs). We identify a previously overlooked pattern (Variable pattern, Var) that multiple enhancers link to the same gene, but rarely coexist in the same cell type. These three patterns control the genes associating with distinct biological function and exhibit unique epigenetic features. Specifically, we discover a subset of Var patterns contains Shared enhancers with stable enhancer-promoter interactions in the majority of cell types, which might contribute to maintaining gene expression by recruiting abundant CTCF.
Together, our findings reveal three distinct E-P regulation patterns across different cell types, providing insights into deciphering the complexity of gene transcriptional regulation.
Trastuzumab resistance followed by metastasis is a major obstacle for improving the clinical outcome of patients with advanced human epidermal growth factor receptor 2-positive (HER-2+) breast ...cancer. While long non-coding RNAs (lncRNAs) can modulate cell behavior, the contribution of these RNAs in trastuzumab resistance and metastasis of HER-2+ breast cancer is not well known. In this study, we sought to identify the regulatory role of lncRNA in trastuzumab resistance and accompanied Epithelial-mesenchymal Transition (EMT) process in advanced HER-2+ breast cancer.
Trastuzumab-resistant SKBR-3-TR and BT474-TR cell lines were established by grafting SKBR-3 and BT474 cells into mouse models and subjected to trastuzumab treatment. LncRNA microarray followed by quantitative reverse transcription PCR (qRT-PCR) was carried out to verify the differentially expressed lncRNAs. Western blotting, bioinformatics analysis, immunofluorescence assay and immunoprecipitation assays (ChIP and RIP) were performed to identify the involvement and functional interactions between H3K27 acetylation and terminal differentiation-induced non-coding RNA (TINCR) or between TINCR and its downstream genes including miR-125b, HER-2 and Snail-1. In addition, a series of in vitro and in vivo assays were performed to assess the functions of TINCR.
An increase in both, IC
value of trastuzumab and EMT was observed in the established trastuzumab-resistant cell lines. The expression level of TINCR was significantly increased in trastuzumab-resistant cells when compared with sensitive cells. Knockdown of TINCR reversed the trastuzumab resistance and the acquired EMT in these cells. TINCR was detected in the cytoplasm of breast cancer cells and could sponge miR-125b, thereby releasing HER-2 and inducing trastuzumab resistance. In addition, Snail-1 was found to be the target gene of miR-125b and overexpression of Snail-1 could reverse the suppressed migration, invasion, and EMT caused by TINCR silencing. The upregulation of TINCR in breast cancer was attributed to the CREB-binding protein (CBP)-mediated H3K27 acetylation at the promoter region of TINCR. Clinically, HER-2+ breast cancer patients with high TINCR expression levels were associated with poor response to trastuzumab therapy and shorter survival time.
TINCR could promote trastuzumab resistance and the accompanied EMT process in breast cancer. Therefore, TINCR might be a potential indicator for prognosis and a therapeutic target to enhance the clinical efficacy of trastuzumab treatment.
MoS
2
microspheres/MOF-derived In
2
S
3
heterostructures were fabricated through a two-step temperature-raising hydrothermal method. MOF-derived In
2
S
3
porous structures were synthesized via a ...sulfidation process of MIL-68(In) precursor, and then MoS
2
microspheres further in situ grew on the surface of In
2
S
3
porous structures at the increased temperature. The as-obtained samples were characterized by XRD, SEM, XPS, UV-Vis DRS, and PL. Compared with pure In
2
S
3
, MoS
2
/In
2
S
3
heterostructures exhibited a higher photocatalytic activity towards methyl orange degradation under visible light irradiation, which should be attributed to the stronger visible light absorption as well as the effective separation of photo-generated electrons and holes.
Highlights
MIL-68(In) is used as the morphological template and the indium precursor.
One-pot synthesis involving a two-step temperature-raising hydrothermal process.
Strong visible light absorption and effective separation of photo-generated carries.
MoS
2
/In
2
S
3
heterostructures exhibit excellent visible-light photocatalytic activity.
Accumulating evidence suggested that epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) characteristics, both of which contribute to tumor invasion and metastasis, are interrelated ...with miR-21. MiR-21 is one of the important microRNAs associated with tumor progression and metastasis, but the molecular mechanisms underlying EMT and CSC phenotype during miR-21 contributes to migration and invasion of breast cancer cells remain to be elucidated.
In this study, MDA-MB-231/anti-miR-21 cells were established by transfected hsa-miR-21 antagomir into breast cancer MDA-MB-231 cells. EMT was evaluated by the changes of mesenchymal cell markers (N-cadherin, Vimentin, and alpha-SMA), epithelial cell marker (E-cadherin), as well as capacities of cell migration and invasion; CSC phenotype was measured using the changes of CSC surface markers (ALDH1 and CD44), and the capacity of sphereforming (mammospheres). We found that antagonism of miR-21 reversed EMT and CSC phenotype, accompanied with PTEN up-regulation and AKT/ERK1/2 inactivation. Interestingly, down-regulation of PTEN by siPTEN suppressed the effects of miR-21 antagomir on EMT and CSC phenotype, confirming that PTEN is a target of miR-21 in reversing EMT and CSC phenotype. The inhibitors of PI3K-AKT and ERK1/2 pathways, LY294002 and U0126, both significantly suppressed EMT and CSC phenotype, indicating that AKT and ERK1/2 pathways are required for miR-21 mediating EMT and CSC phenotype.
In conclusion, our results demonstrated that antagonism of miR-21 reverses EMT and CSC phenotype through targeting PTEN, via inactivation of AKT and ERK1/2 pathways, and showed a novel mechanism of which might relieve the malignant biological behaviors of breast cancer.
•A novel MOF(Fe)@NaAlg aerogels were fabricated via a facile route of ion cross-linking.•The MOF(Fe)@NaAlg aerogels showed excellent loading capability to NH4+.•The N-fertilizers based on ...MOF(Fe)@NaAlg aerogels have displayed the advantages of slow-release and water-retention.
In this work, a novel MOF(Fe)@NaAlg aerogels composite were fabricated by a facile method of ion cross-linking, and characterized via Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric analysis (TG), X-ray photoelectron spectroscopy (XPS) and BET surface area analysis. The MOF(Fe)@NaAlg aerogels loaded by ammonium (NH4+) was prepare to the slow-release fertilizer (SRF). The adsorption capacity and swelling of MOF(Fe)@NaAlg(2:10) were 29.4 mg/g and 73 g/g, respectively. The swelling behaviors of MOF(Fe)@NaAlg(2:10) in different saline solutions were investigated. The release assessments confirmed the effective role of MOF(Fe) in slow-release property of the prepared formulation. Also, the prepared fertilizer formulation exhibited excellent water-retention capacity in soil. Therefore, they will have a great potential application in the field of agriculture.
The morbidity and mortality of sepsis are extremely high, which is a major problem plaguing human health. However, current drugs and measures for the prevention and treatment of sepsis have little ...effect. Sepsis-associated acute liver injury (SALI) is an independent risk factor for sepsis, which seriously affects the prognosis of sepsis. Studies have found that gut microbiota is closely related to SALI, and indole-3-propionic Acid (IPA) can activate Pregnane X receptor (PXR). However, the role of IPA and PXR in SALI has not been reported.
This study aimed to explore the association between IPA and SALI. The clinical data of SALI patients were collected and IPA level in feces was detected. The sepsis model was established in wild-type mice and PXR knockout mice to investigate the role of IPA and PXR signaling in SALI.
We showed that the level of IPA in patients' feces is closely related to SALI, and the level of IPA in feces has a good ability to identify and diagnose SALI. IPA pretreatment significantly attenuated septic injury and SALI in wild-type mice, but not found in knockout PXR gene mice.
IPA alleviates SALI by activating PXR, which reveals a new mechanism of SALI, and provides potentially effective drugs and targets for the prevention of SALI.
Cancer stem cells (CSCs) are predicted to be critical drivers of tumor progression due to their “stemness”, but the molecular mechanism of CSCs in regulating metastasis remains to be elucidated. ...Epithelial‐mesenchymal transition (EMT), hypoxia‐inducible factor (HIF)‐1α, and miR‐21, all of which contribute to cell migration for metastasis, are interrelated with CSCs. In the present study, third‐sphere forming (3‐S) CSC‐like cells, which showed elevated CSC surface markers (ALDH1+ and CD44+/CD24−/low) and sphereforming capacity as well as migration and invasion capacities, were cultured and isolated from breast cancer MCF‐7 parental cells, to evaluate the role of miR‐21 in regulating the CSC‐like cell biological features, especially EMT. EMT, which was assessed by overexpression of mesenchymal cell markers (N‐cadherin, Vimentin, alpha‐smooth muscle actin α‐SMA) and suppression of epithelial cell marker (E‐cadherin), was induced in 3‐S CSC‐like cells. Moreover, both of HIF‐1α and miR‐21 were upregulated in the CSC‐like cells. Interestingly, antagonism of miR‐21 by antagomir led to reversal of EMT, downexpression of HIF‐1α, as well as suppression of invasion and migration, which indicates a key role of miR‐21 involved in regulate CSC‐associated features. In conclusion, we demonstrated that the formation of CSC‐like cells undergoing process of EMT‐like associated with overexpression of HIF‐1α, both of which are regulated by miR‐21. (Cancer Sci 2012; 103: 1058–1064)
The methyltransferase like 3 (METTL3) has been generally recognized as a nuclear protein bearing oncogenic properties. We find predominantly cytoplasmic METTL3 expression inversely correlates with ...node metastasis in human cancers. It remains unclear if nuclear METTL3 is functionally distinct from cytosolic METTL3 in driving tumorigenesis and, if any, how tumor cells sense oncogenic insults to coordinate METTL3 functions within these intracellular compartments. Here, we report an acetylation-dependent regulation of METTL3 localization that impacts on metastatic dissemination. We identify an IL-6-dependent positive feedback axis to facilitate nuclear METTL3 functions, eliciting breast cancer metastasis. IL-6, whose mRNA transcript is subjected to METTL3-mediated m
A modification, promotes METTL3 deacetylation and nuclear translocation, thereby inducing global m
A abundance. This deacetylation-mediated nuclear shift of METTL3 can be counterbalanced by SIRT1 inhibition, a process that is further enforced by aspirin treatment, leading to ablated lung metastasis via impaired m
A methylation. Intriguingly, acetylation-mimetic METTL3 mutant reconstitution results in enhanced translation and compromised metastatic potential. Our study identifies an acetylation-dependent regulatory mechanism determining the subcellular localization of METTL3, which may provide mechanistic clues for developing therapeutic strategies to combat breast cancer metastasis.
"Industry-university-research" collaborative education mode is a kind of personnel training mode that closely combines industry, academia and research. This study aims to explore the reform and ...practice of biological innovation and entrepreneurship education with the goal of improving both ability and quality, and focuses on the application and effect of "industry-university-research" collaborative education mode. Through in-depth analysis of the current situation and problems of biology education, we aim to put forward targeted reform measures and methods to provide useful reference for the development of biology education.
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