Exosomes Derived from Mesenchymal Stem Cells Increase the Viability of Damaged Endometrial Cells via the miR-99b-5p/PCSK9 Axis.

The aim of this article was to investigate whether exosomes derived from bone marrow mesenchymal stem cells repair damaged endometrial stromal cells (EnSCs) through the miR-99b-5p/PCSK9 axis. Exosomes derived from bone marrow mesenchymal stem cells (BMSC-exos) were isolated by ultracentrifugation and characterized using transmission electron microscopy and nanoflow cytometry. A mifepristone-induced EnSC injury model was established in vitro, and the uptake of BMSC-exos was assessed. EnSCs were divided into three groups: the normal group (ctrl), EnSC injury group (model), and BMSC-exo treatment group. The effects of BMSC-exos on EnSC proliferation, apoptosis, and vascular endothelial growth factor (VEGF) expression were assessed by coculturing MSC-exos with endometrial cells. Furthermore, high-throughput sequencing was used to identify differentially expressed genes (DEGs). Through bioinformatics analysis, reverse transcription-quantitative polymerase chain reaction, western blotting, the CCK8 assay, immunohistochemistry, and dual-luciferase experiments, the potential mechanism by which BMSC-exos-derived miRNAs repair EnSC injury was studied. BMSC-exos expressed the marker proteins CD9 and CD63. Laser confocal microscopy showed that BMSC-exos could enter damaged EnSCs. In the BMSC-exos-EnSC coculture group compared with the model group, BMSC-exos significantly increased the proliferation of damaged EnSCs and inhibited cell apoptosis in a dose-dependent manner. The expression levels of Caspase-3, Caspase-9, Bax, and VEGF mRNA were significantly downregulated in the BMSC-exos-EnSC coculture group, whereas Bcl-2 expression was upregulated. We identified 28 overlapping DEGs between the model and ctrl groups and between the BMSC-exo and model groups. Transfection with miR-99b-5p mimics significantly decreased PCSK9 gene expression and inhibited the expression of the autophagy-related proteins Beclin-1 and LC3-II/I and apoptosis, thereby promoting EnSC proliferation. Transfection with a miR-99b-5p inhibitor showed the opposite effects. Beclin-1, LC3-II/I, and PCSK9 expression in the thin endometrium was significantly increased. miR-99b-5p promoted cell proliferation by targeting PCSK9. BMSC-exos promoted endometrial proliferation, and miR-99b-5p inhibited cell apoptosis and promoted EnSC proliferation by targeting PCSK9, providing a new target for the treatment of thin endometrium.

Single-cell analysis reveals alterations in cellular composition and cell-cell communication associated with airway inflammation and remodeling in asthma.

BACKGROUND: Asthma is a heterogeneous disease characterized by airway inflammation and remodeling, whose pathogenetic complexity was associated with abnormal responses of various cell types in the lung. The specific interactions between immune and stromal cells, crucial for asthma pathogenesis, remain unclear. This study aims to determine the key cell types and their pathological mechanisms in asthma through single-cell RNA sequencing (scRNA-seq). METHODS: A 16-week mouse model of house dust mite (HDM) induced asthma (n = 3) and controls (n = 3) were profiled with scRNA-seq. The cellular composition and gene expression profiles were assessed by bioinformatic analyses, including cell enrichment analysis, trajectory analysis, and Gene Set Enrichment Analysis. Cell-cell communication analysis was employed to investigate the ligand-receptor interactions. RESULTS: The asthma model results in airway inflammation coupled with airway remodeling and hyperresponsiveness. Single-cell analysis revealed notable changes in cell compositions and heterogeneities associated with airway inflammation and remodeling. GdT17 cells were identified to be a primary cellular source of IL-17, related to inflammatory exacerbation, while a subpopulation of alveolar macrophages exhibited numerous significantly up-regulated genes involved in multiple pathways related to neutrophil activities in asthma. A distinct fibroblast subpopulation, marked by elevated expression levels of numerous contractile genes and their regulators, was observed in increased airway smooth muscle layer by immunofluorescence analysis. Asthmatic stromal-immune cell communication significantly strengthened, particularly involving GdT17 cells, and macrophages interacting with fibroblasts. CXCL12/CXCR4 signaling was remarkedly up-regulated in asthma, predominantly bridging the interaction between fibroblasts and immune cell populations. Fibroblasts and macrophages could jointly interact with various immune cell subpopulations via the CCL8/CCR2 signaling. In particular, fibroblast-macrophage cell circuits played a crucial role in the development of airway inflammation and remodeling through IL1B paracrine signaling. CONCLUSIONS: Our study established a mouse model of asthma that recapitulated key pathological features of asthma. ScRNA-seq analysis revealed the cellular landscape, highlighting key pathological cell populations associated with asthma pathogenesis. Cell-cell communication analysis identified the crucial ligand-receptor interactions contributing to airway inflammation and remodeling. Our findings emphasized the significance of cell-cell communication in bridging the possible causality between airway inflammation and remodeling, providing valuable hints for therapeutic strategies for asthma.

Structure of the ISW1a complex bound to the dinucleosome.

Nucleosomes are basic repeating units of chromatin and form regularly spaced arrays in cells. Chromatin remodelers alter the positions of nucleosomes and are vital in regulating chromatin organization and gene expression. Here we report the cryo-EM structure of chromatin remodeler ISW1a complex from Saccharomyces cerevisiae bound to the dinucleosome. Each subunit of the complex recognizes a different nucleosome. The motor subunit binds to the mobile nucleosome and recognizes the acidic patch through two arginine residues, while the DNA-binding module interacts with the entry DNA at the nucleosome edge. This nucleosome-binding mode provides the structural basis for linker DNA sensing of the motor. Notably, the Ioc3 subunit recognizes the disk face of the adjacent nucleosome through interacting with the H4 tail, the acidic patch and the nucleosomal DNA, which plays a role in the spacing activity in vitro and in nucleosome organization and cell fitness in vivo. Together, these findings support the nucleosome spacing activity of ISW1a and add a new mode of nucleosome remodeling in the context of a chromatin environment.

Synthesis, molecular docking studies of formononetin derivatives as potent Bax agonists for anticancer activity.

Formononetin as a Bax agonist exhibits anticancer effects. To identify novel Bax agonist, 18 new structurally modified formononetin derivatives were synthesised and their anticancer activities were evaluated in the A549 and Beas-2b cell lines. The results indicated that 7a elicited the most potent inhibitory effect against the A549 cell line, with an IC50 value of 0.87 µM, and no obvious toxicity to Beas-2b cells. These results indicated that 7a was 40-fold and 6.94-fold more efficacious than Formononetin and Doxorubicin, respectively. Additionally, western blot and immunofluorescence assays demonstrated that 7a downregulated the protein expression of Bcl-2 and upregulated the expressions of Bax to promote A549 apoptosis, the obtained results also suggested that 7a had the potential to be developed into a lead compound that can be applied in the prevention and treatment of lung cancer.

Reconfigurable coaxial single-photon LIDAR based on the SPAD array.

The single-photon avalanche diode (SPAD) array with time-to-digital converter (TDC) circuits on each pixel is an excellent candidate detector for imaging LIDAR systems. However, the low fill-factor of the SPAD array does not allow for efficient use of laser energy when directly adopted in a LIDAR system. Here, we design a reconfigurable coaxial single-photon LIDAR based on the SPAD array and diffractive optical elements (DOEs). We use the DOE and beam expander to shape the laser beam into a laser dot matrix. The total divergence angle of the DOE spot beam is strictly matched to the total field of view (FOV) angle of the SPAD array. Meanwhile, each focused beamlet is individually matched to every active area of the SPAD array detector, which increases the use of output energy about 100 times compared to the diffusion illumination system. Besides, the system uses the active area as the minimum pixel and can support sub-pixel scanning, resulting in higher resolution images. Through this coaxial structure, two different telescope systems after transceiver switching can be reconfigured for imaging targets at different distances. Based on our single-photon LIDAR system, we achieved 3D imaging of targets at 100 m and 180 m using two different telescope configurations.

Urban-rural differences in epidemiology and risk factors of menopause syndrome in middle-aged Chinese women.

OBJECTIVE: To compare the prevalence and severity of menopausal symptoms and investigate their associated factors among rural and urban middle-aged Chinese women. METHODS: A descriptive, cross-sectional study of 4,580 urban and 2,729 rural randomly sampled participants aged 40 to 55 years in Gansu Province, China, was conducted. Questionnaires assessing the sociodemographic information and menstrual and reproductive histories of the participants were administered. The modified Kupperman scale was used to assess the presence and severity of menopausal symptoms. Binary and ordinal logistic regression analyses were performed to identify factors associated with the occurrence and severity of menopausal syndrome, respectively, according to the modified Kupperman Menopausal Index score rank. RESULTS: The natural menopausal age of the rural women was significantly lower than that of the urban women (rural: 47.22, urban: 47.98; P < 0.05). Furthermore, rural women had a higher prevalence (rural: 56.35%, urban: 43.47%) and severity (rural: 11.40%, urban: 6.61%) of menopausal syndrome than the urban women ( P < 0.05). For both the urban and rural women, the prevalence and severity of most menopausal symptoms increased as menopause progressed. The three most prevalent symptoms in both the urban and rural women were fatigue (rural: 70.43%, urban: 68.19%), muscle/joint pain (rural: 62.84%, urban: 59.32%), and vertigo (rural: 57.42%, urban: 47.44%). Positive associations between menopausal symptoms and age, residence, body mass index, level of education, time of pregnancy, menstrual cycle, and presence of chronic diseases were observed. CONCLUSIONS: Rural women experience more frequent and severe menopausal syndrome than do urban women.

Progress of oxidative stress in endometrium decidualization.

The difficulty in maintaining the balance between oxides and antioxidants causes a phenomenon named oxidative stress. Oxidative stress often leads to tissue damage and participates in the pathogenesis of a series of diseases. Decidua provides the 'soil' for embryo implantation, and the normal decidualization shows the characteristics of strong antioxidation. Once the mechanism of antioxidant stress goes awry, it will lead to a series of pregnancy-related diseases. In recent years, more and more studies have shown that oxidative stress is involved in pregnancy-related diseases caused by abnormal decidualization of the endometrium. In order to have a more comprehensive understanding of the role of oxidative stress in decidual defect diseases, this paper reviews the common decidual defect diseases in conjunction with relevant regulatory molecules, in order to arouse thinking about the importance of oxidative stress, and to provide more theoretical basis for the aetiology of decidual defects.

High-resolution depth imaging with a small-scale SPAD array based on the temporal-spatial filter and intensity image guidance.

Currently single-photon avalanche diode (SPAD) arrays suffer from a small-scale pixel count, which makes it difficult to achieve high-resolution 3D imaging directly through themselves. We established a CCD camera-assisted SPAD array depth imaging system. Based on illumination laser lattice generated by a diffractive optical element (DOE), the registration of the low-resolution depth image gathered by SPAD and the high-resolution intensity image gathered by CCD is realized. The intensity information is used to guide the reconstruction of a resolution-enhanced depth image through a proposed method consisting of total generalized variation (TGV) regularization and temporal-spatial (T-S) filtering algorithm. Experimental results show that an increasement of 4 × 4 times for native depth image resolution is achieved and the depth imaging quality is also improved by applying the proposed method.

Autologous platelet-rich plasma intrauterine perfusion to improve pregnancy outcomes after implantation failure: A systematic review and meta-analysis.

AIMS: Previous studies have reported inconsistent findings on the efficacy of platelet-rich plasma (PRP) therapy in women with implantation failure. The objective of this review was to evaluate whether PRP administration could improve pregnancy outcomes in women with implantation failure undergoing in vitro fertilization. METHODS: Electronic databases were searched for studies that explored the effects of PRP for patients with implantation failure. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Based on the available data, we performed subgroup analyses and sensitivity analyses. RESULTS: Eight studies were included. PRP treatment improved pregnancy outcomes for all women compared with no treatment or placebo (clinical pregnancy rate: OR 2.24, 95% CI 1.41-3.54; live birth rate: OR 5.76, 95% CI 1.55-21.44; miscarriage rate: OR 0.18, 95% CI 0.05-0.63), especially in randomized controlled trials. No significant differences were detected in multiple pregnancy rates (OR 2.54, 95% CI 0.67-9.67). Furthermore, subgroup analysis based on the number of previous implantation failures showed that PRP treatment improved pregnancy outcomes in women with recurrent implantation failure (clinical pregnancy rate: OR 2.55, 95% CI 1.49-4.38; live birth rate: OR 5.07, 95% CI 1.15-22.34; miscarriage rate: OR 0.20, 95% CI 0.05-0.78). CONCLUSION: PRP administration could improve pregnancy outcomes in women with recurrent implantation failure. Due to the limited evidence available, the efficacy of PRP in women with recurrent implantation failure needs to be further verified in high-quality studies with larger sample sizes.

Cellular sources of airway smooth muscle cells in asthmatic airway remodeling and their clinical relevance: a narrative review.

Background and Objective: Airway remodeling in asthma refers to numerous structural changes in the airway in asthmatic patients, with thickening of the airway smooth muscle layer as its core feature. However, the nature and sources of the abnormally increased airway smooth muscle cells (ASMCs) in airway remodeling remain unclear. ASMCs play a key role in the pathogenesis of fatal asthma; therefore, it is important to clarify the properties and sources of these ASMCs responsible for asthmatic airway remodeling, which may provide a new direction for the precise treatment for asthma. Methods: We performed a narrative review of the literature on PubMed, Web of Science, and Google Scholar databases searching for the cellular sources of ASMCs in asthmatic airway remodeling and their clinical relevance. Key Content and Findings: It has long been thought that ASMCs are the result of abnormal proliferation of the native ASMCs in asthma; however, increasing evidence suggests that increased "ASMCs" may be due to the differentiation/transdifferentiation of other cells including mesenchymal stem cells (MSCs), myofibroblasts (MYFs), pericytes, and epithelial-mesenchymal transition (EMT). Recently, several pharmacological and biological therapies aimed at "reducing asthmatic ASMCs" have been developed, among which gallopamil, JQ1 [an inhibitor of the bromodomain and extra-terminal domain (BET) protein family], and histone deacetylase (HDAC) inhibitors can alleviate asthma airway remodeling and hyperresponsiveness and improve asthma symptoms in both mouse models and preclinical experiments. Conclusions: As one of the core features of asthma, ASMCs are an important effector of airway remodeling. It has become extremely important to develop therapies for the reduction and prevention of the "ASMCs" on the basis of the properties and sources of "ASMCs". Many studies have shown that epigenetic regulation is closely related to the abnormal increase of ASMCs in asthma, and interfering with epigenetic regulation factors can reduce the increased smooth muscle cells. Although the epigenetic regulation of asthma is still in its nascent stage, epigenetic therapy targeting "ASMCs" may become another new strategy for asthma prevention and treatment.

Clinical outcomes of personalized frozen-thawed embryo transfer timing for patients with recurrent implantation failure.

Background: Recurrent implantation failure (RIF) is a critical problem for assisted reproduction technology. High-quality embryos and the synchronization endometrium both have great significance. How to get the optimal endometrial receptivity is a challenge for implantation and pregnancy of infertile patients with RIF. The objective of this study is to investigate personalized protocol of frozen-thawed embryo transfer (FET) cycles, and its effect on clinical outcomes in patients with RIF. Methods: We chose 91 RIF patients from January 2017 to June 2019 in the Reproductive Medicine Center of the First Hospital of Lanzhou University. A total of 100 FET cycles were undertaken with a gonadotropin-releasing hormone agonist (GnRH-agonist) protocol combined with hormone replacement therapy (HRT) for endometrial preparation. The patients were divided into two groups: the routine group (cleavage embryo transferred at day 3 after luteal support) included 48 cycles; the personalized group included 52 cycles with delayed endometrial trigger and luteal support (the time of embryo transfer depended on the level of serum hormone and endometrial thickness). Results: The data showed the personalized group had longer time for endometrial preparation. On the day of embryo transfer, serum progesterone (P) and the E2/P ratio was significantly different compared with the routine group (P<0.05). The clinical pregnancy rate in the routine group was 35.42% (17/48) and 59.62% (31/52) in the personalized group (P<0.05). The abortion rate was not significantly different. Conclusions: For women with RIF, personalized timing for transfer of FET resulted in a higher clinical pregnancy rate compared with routine protocol.

GnRH agonist treatment regulates IL-6 and IL-11 expression in endometrial stromal cells for patients with HRT regiment in frozen embryo transfer cycles.

To evaluate the effect of gonadotropin-releasing hormone agonist (GnRHa) pretreatment time on clinical outcomes of patients who underwent endometrial preparation in HRT cycles and the molecular mechanism in frozen-thawed embryo transfer (FET) cycles, we retrospectively chose 1143 cycles and separated four groups. Endometrial tissues were collected from 44 patients who were cancelled on the day of embryo transfer (there were 10 patients refused to collect endometrium) and were tested for endometrial receptivity marker mRNA and miR-124-3p expression. Furthermore, endometrial stromal cells (ESCs) were transfected to investigate the molecular mechanism. The clinical pregnancy rate and live birth rate were significantly high in group B. The endometrial expression of the IL-6 and IL-11 mRNAs was significantly increased in groups with GnRHa pretreatment compared with group A without the GnRHa pretreatment. Similar results were obtained for the endometrial receptivity markers LIF and integrin αvß3. The groups treated with GnRHa exhibited a progressive and significant time-dependent decrease in the IL-6 and IL-11 mRNA. In contrast, the levels of LIF and integrin αvß3 expression remained unaltered among group B-D. In addition, transfection of ESCs with miR-124-3p mimics significantly reduced levels of the IL-6 and IL-11 mRNAs and proteins. The luciferase report assay demonstrated that IL-6 and IL-11 is a target gene of miR-124-3p. The results showed that ultra-long GnRHa administration can improve outcomes, especially after 3 cycles of GnRHa pretreatment, and endometrial receptivity through IL-6 and IL-11 expression levels of ESC regulated by the miR-124-3p for patients with HRT, who underwent FET cycles.

Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition.

Epithelial-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to modulate proliferation, migration, and stress response. Whereas kinase signaling is believed to be an EMT driver, the molecular mechanisms underlying epithelial-mesenchymal interconversion are incompletely understood. Here, we show that the impact of chromatin regulators on EMT interconversion is broader than that of kinases. By combining pharmacological modulation of EMT, synthetic genetic tracing, and CRISPR interference screens, we uncovered a minority of kinases and several chromatin remodelers, writers, and readers governing homeostatic EMT in lung cancer cells. Loss of ARID1A, DOT1L, BRD2, and ZMYND8 had nondeterministic and sometimes opposite consequences on epithelial-mesenchymal interconversion. Together with RNAPII and AP-1, these antagonistic gatekeepers control chromatin of active enhancers, including pan-cancer-EMT signature genes enabling supraclassification of anatomically diverse tumors. Thus, our data uncover general principles underlying transcriptional control of cancer cell plasticity and offer a platform to systematically explore chromatin regulators in tumor-state-specific therapy.

Curcusone C induces apoptosis in endometrial cancer cells via mitochondria-dependent apoptotic and ERK pathway.

OBJECTIVE: Jatropha curcashas been used in traditional medicine in Africa to treat cancer for thousands of years. This study aimed to examine the anti-endometrial cancer effect of Curcusone C, a naturally occurring rhamnofolane diterpene, isolated from J. curcas and reveal its molecular mechanism of action. RESULTS: Curcusone C treatment caused significant anti-proliferative and apoptotic effects in human endometrial cancer (EC) Ishikawa and HEC-1A cells in a dose-dependent manner. Exposure of EC cells to Curcusone C resulted in apoptosis, which was associated with cytochrome c release, caspase-3 and caspase-9 activation, Bcl-xL/Bax dysregulation, and decreased expression of inhibitors of apoptosis proteins, such as XIAP and survivin. The inhibitory effect induced by Curcusone C was greatly impaired by the overexpression of survivin or Bax-/- MEFs or the knockdown of Bim expression. Moreover, Curcusone C activated mitogen-activated protein kinases, and the ERK inhibitor U0126 significantly attenuated the growth-inhibitory and apoptotic effects of Curcusone C in Ishikawa cells. CONCLUSION: Taken together, the results demonstrate the anti-endometrial cancer potential of Curcusone C for the treatment of endometrial cancer.

Decreased expression of m6A demethylase FTO in ovarian aging.

PURPOSE: N6-methyladenosine (m6A) and demethylase fat mass and obesity-associated protein (FTO) were reported to be associated with oocyte development and maturation. But the relationship between FTO and ovarian aging was still unclear. This study was aimed at investigating the FTO expression level and the m6A content during ovarian aging. METHODS: The expression level of FTO and the content of m6A RNA methylation in human follicular fluid (FF), granulosa cells (GCs) and mouse ovary from different age groups were studied by ELISA, WB, qRT-PCR, IHC and m6A Colorimetric. RESULTS: Human FF ELISA quantified that the level of FTO protein decreased with age (P = 0.025). QRT-PCR results showed that the relative expression of FTO in human GCs was lower in the elderly group than in the young group (P = 0.012). FTO mRNA and protein expression levels were lower in the ovary of 32-week-old mice than in 3- and 8-week-old mice (P < 0.05). Immunohistochemistry showed FTO was relatively decreased in 32-week-old mice (P < 0.05). The m6A content in total RNA from old human GCs and ovary from 32-week-old mice was significantly higher compared with the younger ones. CONCLUSIONS: In human FF, GCs and mouse ovary, the expression of FTO decreased while the content of m6A increased with aging. However, the inner mechanism still needs further investigation.

A clinical and basic study of optimal endometrial preparation protocols for patients with infertility undergoing frozen-thawed embryo transfer.

The optimal protocol for endometrial preparation in patients with infertility remains unclear. Due to this, the current study retrospectively analyzed 1,589 patients with infertility and regular menstrual cycles to assess reproductive outcomes per embryo transferred and per embryo transfer (ET) cycle following the transfer of frozen-thawed embryos (FET) in a modified natural cycle (mNC) or hormone therapy cycle (HT) with or without gonadotropin-releasing hormone agonist (GnRHa)-induced pituitary suppression. The molecular mechanisms involved were also studied using tissues from endometrial biopsies. Patients who underwent FET were assigned to 5 groups as follows: Group A underwent a mNC (n=276); group B (n=338) received estradiol (E2) and progesterone (P4); group C received 1 cycle of GnRHa, E2 and P4 (n=323); group D received 2 cycles of GnRHa, E2 and P4 (n=329); and group E received 3 cycles of GnRHa, E2 and P4 (n=323). Tissues from endometrial biopsies of 91 patients performed on the day of ET were tested for endometrial receptivity marker mRNA expression and microRNA (miR)-223-3p mRNA. Furthermore, endometrial stromal cells (ESCs) were used for an in-depth study of the molecular mechanisms involved. Among the 5 groups of patients, implantation rates, clinical pregnancy rates and live birth rates were not significantly different. However, endometrial receptivity was enhanced in group E when compared with groups A-D, which was associated with endometrial leukemia inhibitory factor (LIF), osteopontin, vascular endothelial growth factor, integrin ß3 and homeobox gene 10 and 11 mRNA upregulation, and miR-223-3p miRNA downregulation. Transfection of ESCs with an miR-223-3p mimic significantly reduced levels of LIF mRNA and protein. In addition, pre-treating ESCs with GnRHa upregulated mRNA and protein expression of the decidualization markers prolactin and insulin-like growth factor binding protein-1 in a time-dependent manner. In conclusion, these results indicated that HT with GnRHa may be a potential endometrial preparation protocol for FET.

circRNA-14723 promotes hepatocytes proliferation in rat liver regeneration by sponging rno-miR-16-5p.

Circular RNA (circRNA) is a subclass of noncoding RNA (ncRNA) detected within mammalian tissues and cells. However, its regulatory role during the proliferation phase of rat liver regeneration (LR) remains unreported. This study was designed to explore their regulatory mechanisms in cell proliferation of LR. The circRNA expression profile was detected by high-throughput sequencing. It was indicated that 260 circRNAs were differentially expressed during the proliferation phase of rat LR. Among them, circ-14723 displayed a significantly differential expression. We further explored its regulatory mechanism in rat hepatocytes (BRL-3A cells). First, EdU, flow cytometry and western blot (WB) indicated that knocking down circ-14723 inhibited BRL-3A cells proliferation. Second, RNA-Pulldown and dual-luciferase report assay showed that circ-14723 could sponge rno-miR-16-5p. At last, WB showed that the reported target genes of rno-miR-16-5p, CCND1, and CCNE1 were downregulated after knocking down circ-14723. In conclusion, we found that circ-14723 exerted a critical role in G1/S arrest to promote cell proliferation via rno-miR-16-5p/CCND1 and CCNE1 axis in rat LR. This finding further revealed the regulatory mechanisms of circRNA on cell proliferation of LR, and might provide a potential target for clinical problems.

Independent Transposon Exaptation Is a Widespread Mechanism of Redundant Enhancer Evolution in the Mammalian Genome.

Many regulatory networks appear to involve partially redundant enhancers. Traditionally, such enhancers have been hypothesized to originate mainly by sequence duplication. An alternative model postulates that they arise independently, through convergent evolution. This mechanism appears to be counterintuitive to natural selection: Redundant sequences are expected to either diverge and acquire new functions or accumulate mutations and become nonfunctional. Nevertheless, we show that at least 31% of the redundant enhancer pairs in the human genome (and 17% in the mouse genome) indeed originated in this manner. Specifically, for virtually all transposon-derived redundant enhancer pairs, both enhancer partners have evolved independently, from the exaptation of two different transposons. In addition to conferring robustness to the system, redundant enhancers could provide an evolutionary advantage by fine-tuning gene expression. Consistent with this hypothesis, we observed that the target genes of redundant enhancers exhibit higher expression levels and tissue specificity as compared with other genes. Finally, we found that although enhancer redundancy appears to be an intrinsic property of certain mammalian regulatory networks, the corresponding enhancers are largely species-specific. In other words, the redundancy in these networks is most likely a result of convergent evolution.