Histone 3 Lys 27 trimethylation (H3K27me3)-mediated epigenetic silencing plays a critical role in multiple biological processes. However, the H3K27me3 recognition and transcriptional repression mechanisms are only partially understood. Here, we report a mechanism for H3K27me3 recognition and transcriptional repression. Our structural and biochemical data showed that the BAH domain protein AIPP3 and the PHD proteins AIPP2 and PAIPP2 cooperate to read H3K27me3 and unmodified H3K4 histone marks, respectively, in Arabidopsis. The BAH-PHD bivalent histone reader complex silences a substantial subset of H3K27me3-enriched loci, including a number of development and stress response-related genes such as the RNA silencing effector gene ARGONAUTE 5 (AGO5). We found that the BAH-PHD module associates with CPL2, a plant-specific Pol II carboxyl terminal domain (CTD) phosphatase, to form the BAH-PHD-CPL2 complex (BPC) for transcriptional repression. The BPC complex represses transcription through CPL2-mediated CTD dephosphorylation, thereby causing inhibition of Pol II release from the transcriptional start site. Our work reveals a mechanism coupling H3K27me3 recognition with transcriptional repression through the alteration of Pol II phosphorylation states, thereby contributing to our understanding of the mechanism of H3K27me3-dependent silencing.
Background: The KRAS mutation is the second most common genetic variant in Chinese non-small cell lung cancer (NSCLC) patients. At the 2019th World Conference of Lung Cancer, the KRAS G12C-specific inhibitor AMG510 showed promising results in the phase I clinical trial. However, the frequency, clinical characteristics, and prognostic significance of the KRAS G12C mutation in Chinese NSCLC patients are rarely reported. Methods: Next-generation sequencing was used to confirm the KRAS mutation status in 40,804 NSCLC patients from multiple centers (mCohort). Survival data were collected retrospectively from 1456 patients at one of the centers, the Guangdong Lung Cancer Institute (iCohort). Results: In the mCohort, 3998 patients (9.8%) were confirmed to harbor a KRAS mutation, of whom 1179 (29.5%) had the G12C subtype. In the iCohort, 130 NSCLC patients (8.9%) had a KRAS mutation and 42 (32.3%) had the G12C subtype. The G12C subgroup included more male patients (85.2% vs 67.4%, P < 0.0001) and more smokers (76.2% vs 53.4%, P = 0.02) than did the non-G12C subgroup. Both the KRAS mutation group and KRAS G12C mutation subgroup were associated with a shorter median overall survival (OS) than wildtype tumors (15.1 vs 26.7 months, hazard ratio [HR] KRAS = 1.50, P = 0.002; 18.3 vs 26.7 months, HR G12C = 1.66, P = 0.007). In Cox regression analysis, smoking (HR = 1.39, P = 0.05) and stage IV disease (HR = 2.72, P < 0.001) remained as independent predictors of shorter OS. Both the KRAS mutation (HR = 1.30, P = 0.07) and KRAS G12C mutation (HR = 1.47, P = 0.07) reached borderline significance. Conclusions: In the largest sample used thus for, our study found that approximately 10% of Chinese NSCLC patients had KRAS mutations. Of these, nearly 30% harbored the KRAS G12C mutation subtype, which was most common in male smokers. The KRAS G12C mutation is a biomarker of poor prognosis in Chinese NSCLC patients, which could potentially be improved by G12C-specific inhibitors in the future.
A novel lateral flow immunoassay (LFIA) signal amplification strategy for the detection of Cry1Ab based on amplification via a polylysine (PL) chain and biotin-streptavidin system (BSAS) is described. In this system, multiple fluorescence dyes (FL) were directly coated on the surface of PL and conjugated with antibody via the BSAS for construction of novel signal amplification (FLPL-BSAS-mAb1) conjugates, in which FL, PL and BSAS were employed to improve the sensitivity of LFIA. Compared with conventional LFIA, the sensitivity of FLPL-BSAS-mAb1-based LFIA was increased by approximately 100-fold. Quantified linearity was achieved in the value range of 0–1,000 pg/mL. The limit of detection (LOD) was reached 10 pg/mL after optimization of reaction conditions. To our knowledge, this represents one of the most sensitive LFIA for Cry1Ab yet reported. Furthermore, the detection time for this method was about 10 min. Therefore, it should be an attractive alternative compared to conventional immunoassays in routine control for Cry1Ab.
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