反馈回路是维持机体稳态最重要的机制之一，近年来它的中标率也逐步增加。本喵今天看了很多关于反馈回路的高分文章，拿了3篇有代表性的跟大家探讨一下。

1、Nucleation and propagation of heterochromatin by the histone methyltransferase PRC2: geometric constraints and impact of the regulatory subunit JARID2.

J Am Chem Soc1区. 

分子机制：多梳抑制复合物2（PRC2），可对H3K27三甲基化（H3K27me3），是肿瘤发生发展的一部分，和/或维持成人组织特异性。PRC2癌症中的关键作用使它成为表观遗传学癌症治疗的治疗靶点。其主要的功能在于沉默阻止某些基因的转录表达，而其自身是有多个亚基组成的，包括什么呢？H3K27me3的形成是由多梳蛋白抑制复合物2（PRC2）介导的。PRC2的核心组分是EED、SUZ12、EZH1和EZH2，其中EZH1和EZH2是具有H3K27甲基转移酶的功能。而PRC2的亚基JARID2可调控甲基化的形成速度，作者的研究表明JARID2的磷酸化可影响PRC2的活性，而H3K27甲基化的位置又反馈给PRC2调控信息，形成正反馈回路。

摘要：Polycomb Repressive Complex 2 (PRC2) catalyzes mono-, di-, and trimethylation of lysine 27 on histone H3 (H3K27me1-3) to control expression of genes important for differentiation and maintenance of cell identity. PRC2 activity is regulated by a number of different inputs, including allosteric activation by its product, H3K27me3. This positive feedback loop is thought to be important for the establishment of large domains of condensed heterochromatin. In addition to other chromatin modifications, ancillary subunits of PRC2, foremost JARID2, affect the rate of H3K27 methylation. Many gaps remain in our understanding of how PRC2 integrates these various signals to determine where and when to deposit H3K27 methyl marks. In this study, we utilize designer chromatin substrates to demonstrate that propagation of H3K27 methylation by the PRC2 core complex has geometrically defined preferences that are overridden by the presence of JARID2. Our studies also show that phosphorylation of JARID2 can regulate its ability to stimulate PRC2 activity. Collectively, these biochemical insights further our understanding of the mechanisms that govern PRC2 activity, and highlight a role for JARID2 in de novo deposition of H3K27me3-containing repressive domains.

2、Histone chaperone FACT complex mediates oxidative stress response to promote liver cancer progression.

Gut1区.

分子机制：在芽细胞中，FACT（facilitates chromatin transactions）蛋白参与新生 H3-H4 的核小体组装。组蛋白伴侣复合物 FACT 包含 Spt16 和 SSRP1（在酵母中为 Pob3），能与四种经典的组蛋白结合。FACT 通过与 H2A-H2B 相互作用而部分参与核小体重组，尤其是在转录和 DNA 复制中发挥重要作用。作者研究发现FACT复合物在HCC癌样本中上调表达，而氧化应激压力通过调控KEAP1接到的泛素化修饰降解，可阻断NRF2以及FACT的丰度，Nrf2是一个转录因子，全称是「nuclear factor erythroid-2-related factor 2」，每个人身体里都有它，不过它确实是我们身体中的一个非常重要的健康枢纽呢。Nrf2尤为重要的作用是，它能激活多种抗氧化酶（如谷胱甘肽过氧化物酶和硫氧还还原酶），来清除身体中过多的氧化自由基。而NRF2在本研究中和FACT复合物形成正反馈回路：NRF2促进了FACT亚基的转录，而FACT又促进了NRF2的转录延伸过程，以及通过激活核小体的组装促进其下游的抗氧化的关键基因。

用于治疗乳腺癌的CURAXIN能阻断HCC，增加肝癌对索拉非尼敏感性。

摘要：

RESULTS: We showed that FACT complex was remarkably upregulated in HCC and contributed to HCC progression. Importantly, we unprecedentedly revealed an indispensable role of FACT complex in NRF2-driven oxidative stress response. Oxidative stress prevented NRF2 and FACT complex from KEAP1-mediated protein ubiquitination and degradation. Stabilised NRF2 and FACT complex form a positive feedback loop; NRF2 transcriptionally activates the FACT complex, while FACT complex promotes the transcription elongation of NRF2 and its downstream antioxidant genes through facilitating rapid nucleosome disassembly for the passage of RNA polymerase. Therapeutically, Curaxin effectively suppressed HCC growth and sensitised HCC cell to sorafenib.

CONCLUSION: In conclusion, our findings demonstrated that FACT complex is essential for the expeditious HCC oxidative stress response and is a potential therapeutic target for HCC treatment.

3、Let-7a-regulated translational readthrough of mammalian AGO1 generates a microRNA pathway inhibitor.

Singh A, Manjunath LE, Kundu P, Sahoo S, Das A, Suma HR, Fox PL, Eswarappa SM.

EMBO J1区. 

分子机制：这篇文章关于miRNA，然后argonaute (AGO)：AGO蛋白质主要包含两个结构域：PAZ和PIWI两个结构域，对于siRNA和目标mRNA相互作用，从而导致目标mRNA的切割或者翻译抑制过程，是必不可少的。人工合成了AGO1 mRNA的同源物AGO1x，其上面 有一个miRNA let-7a的结合序列，有趣的是Ago1x蛋白可以将miRNAs们加载到靶向mRNA上，但是不会造成显著的基因沉默现象，因为Ago1x无法和GW182结合，据此Ago1x可以作为miRNA通路的抑制剂，可以观察到Ago1x和miRNA形成负反馈调控环路。

摘要：Translational readthrough generates proteins with extended C-termini, which often possess distinct properties. Here, we have used various reporter assays to demonstrate translational readthrough of AGO1 mRNA. Analysis of ribosome profiling data and mass spectrometry data provided additional evidence for translational readthrough of AGO1. The endogenous readthrough product, Ago1x, could be detected by a specific antibody both in vitro and in vivo. This readthrough process is directed by a cis sequence downstream of the canonical AGO1 stop codon, which is sufficient to drive readthrough even in a heterologous context. This cis sequence has a let-7a miRNA-binding site, and readthrough is promoted by let-7a miRNA. Interestingly, Ago1x can load miRNAs on target mRNAs without causing post-transcriptional gene silencing, due to its inability to interact with GW182. Because of these properties, Ago1x can serve as a competitive inhibitor of miRNA pathway. In support of this, we observed increased global translation in cells overexpressing Ago1x. Overall, our results reveal a negative feedback loop in the miRNA pathway mediated by the translational readthrough product of AGO1

2022年度国自然医学部国自然40大科研热点的中标数统计如下：