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  • LETTER
    Mengyue Lv, Dan Cao, Liwen Zhang, Chi Hu, Shukai Li, Panrui Zhang, Lianbang Zhu, Xiao Yi, Chaoliang Li, Alin Yang, Zhentao Yang, Yi Zhu, Kaiguang Zhang, Wen Pan
  • REVIEW
    Hui Yang, Bruce Beutler, Duanwu Zhang

    Precursor messenger RNA (pre-mRNA) splicing is catalyzed by an intricate ribonucleoprotein complex called the spliceosome. Although the spliceosome is considered to be general cell “housekeeping” machinery, mutations in core components of the spliceosome frequently correlate with cellor tissue-specific phenotypes and diseases. In this review, we expound the links between spliceosome mutations, aberrant splicing, and human cancers. Remarkably, spliceosome-targeted therapies (STTs) have become efficient anti-cancer strategies for cancer patients with splicing defects. We also highlight the links between spliceosome and immune signaling. Recent studies have shown that some spliceosome gene mutations can result in immune dysregulation and notable phenotypes due to missplicing of immune-related genes. Furthermore, several core spliceosome components harbor splicing-independent immune functions within the cell, expanding the functional repertoire of these diverse proteins.

  • RESEARCH ARTICLE
    Hui Zhang, Jiaming Li, Jie Ren, Shuhui Sun, Shuai Ma, Weiqi Zhang, Yang Yu, Yusheng Cai, Kaowen Yan, Wei Li, Baoyang Hu, Piu Chan, Guo-Guang Zhao, Juan Carlos Izpisua Belmonte, Qi Zhou, Jing Qu, Si Wang, Guang-Hui Liu
    Protein & Cell, 2021, 12(9): 695-716. https://doi.org/10.1007/s13238-021-00852-9

    The hippocampus plays a crucial role in learning and memory, and its progressive deteriorationwith age is functionally linked to a variety ofhuman neurodegenerative diseases.Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal unction along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the agedmicroglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.

  • LETTER
    Ni Zong, Min Wang, Yinghui Fu, Dan Shen, Yong-Chun Yu
  • REVIEW
    Linchong Sun, Huafeng Zhang, Ping Gao

    Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolismand epigenetic modification-based therapeutic prospects in cancer.

  • RECOLLECTION
    Yong Wang, Wei Chen, Shiying Li, Bin Yin
  • RECOLLECTION
    Wei Xie, Ben-Yu Guo, Yanyan Qian
  • COMMENTARY
    Hang-Yu Zhou, Cheng-Yang Ji, Hang Fan, Na Han, Xiao-Feng Li, Aiping Wu, Cheng-Feng Qin
  • LETTER
    Beili Chen, Jianying Guo, Ting Wang, Qianhui Lee, Jia Ming, Fangfang Ding, Haitao Li, Zhiguo Zhang, Lin Li, Yunxia Cao, Jie Na
  • LETTER
    Xingdong Zhou, Hui Wang, Qun Ji, Mingjuan Du, Yuexia Liang, Huanhuan Li, Fan Li, Hang Shang, Xiujuan Zhu, Wei Wang, Lichun Jiang, Alexey V. Stepanov, Tianyu Ma, Nanxin Gong, Xiaodong Jia, Alexander G. Gabibov, Zhiyong Lou, Yinying Lu, Yu Guo, Hongkai Zhang, Xiaoming Yang
  • HIGHLIGHT
    Victoria E. von Saucken, David J. Simon
    Protein & Cell, 2021, 12(8): 596-598. https://doi.org/10.1007/s13238-021-00842-x
  • REVIEW
    Xiya Zhang, Tao Li, Jianping Ou, Junjiu Huang, Puping Liang

    Recent advances in genome editing, especially CRISPRCas nucleases, have revolutionized both laboratory research and clinical therapeutics. CRISPR-Cas nucleases, together with the DNA damage repair pathway in cells, enable both genetic diversification by classical non-homologous end joining (c-NHEJ) and precise genome modification by homology-based repair (HBR). Genome editing in zygotes is a convenient way to edit the germline, paving the way for animal disease model generation, as well as human embryo genome editing therapy for some life-threatening and incurable diseases. HBR efficiency is highly dependent on the DNA donor that is utilized as a repair template. Here, we review recent progress in improving CRISPR-Cas nuclease-induced HBR in mammalian embryos by designing a suitable DNA donor. Moreover, we want to provide a guide for producing animal disease models and correcting genetic mutations through CRISPR-Cas nuclease-induced HBR in mammalian embryos. Finally, we discuss recent developments in precise genomemodification technology based on the CRISPR-Cas system.

  • RESEARCH ARTICLE
    Chuan Chen, Wenqiang Liu, Jiayin Guo, Yuanyuan Liu, Xuelian Liu, Jun Liu, Xiaoyang Dou, Rongrong Le, Yixin Huang, Chong Li, Lingyue Yang, Xiaochen Kou, Yanhong Zhao, You Wu, Jiayu Chen, Hong Wang, Bin Shen, Yawei Gao, Shaorong Gao
    Protein & Cell, 2021, 12(6): 455-474. https://doi.org/10.1007/s13238-021-00837-8

    N6-methyladenosine (m6A) on chromosome-associated regulatory RNAs (carRNAs), including repeat RNAs, plays important roles in tuning the chromatin state and transcription, but the intrinsic mechanism remains unclear. Here, we report that YTHDC1 plays indispensable roles in the self-renewal and differentiation potency of mouse embryonic stem cells (ESCs), which highly depends on the m6A-binding ability. Ythdc1 is required for sufficient rRNA synthesis and repression of the 2-cell (2C) transcriptional program in ESCs, which recapitulates the transcriptome regulation by the LINE1 scaffold. Detailed analyses revealed that YTHDC1 recognizes m6A on LINE1 RNAs in the nucleus and regulates the formation of the LINE1-NCL partnership and the chromatin recruitment of KAP1. Moreover, the establishment of H3K9me3 on 2C-related retrotransposons is interrupted in Ythdc1-depleted ESCs and inner cell mass (ICM) cells, which consequently increases the transcriptional activities. Our study reveals a role of m6A in regulating the RNA scaffold, providing a new model for the RNA-chromatin cross-talk.

  • REVIEW
    Guang Lei, Chao Mao, Yuelong Yan, Li Zhuang, Boyi Gan

    Ferroptosis, an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes, has recently been revealed to play an important role in radiotherapy-induced cell death and tumor suppression, and to mediate the synergy between radiotherapy and immunotherapy. In this review, we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and ferroptosis, discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy, and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and immunotherapy. This review will provide important frameworks for future investigations of ferroptosis in cancer therapy.

  • RESEARCH ARTICLE
    Yue Sun, Qi Wang, Yi Wang, Wenran Ren, Ying Cao, Jiali Li, Xin Zhou, Wei Fu, Jing Yang
    Protein & Cell, 2021, 12(8): 621-638. https://doi.org/10.1007/s13238-021-00835-w

    Axonal degeneration is one of the key features of neurodegenerative disorders. In the canonical view, axonal degeneration destructs neural connections and promotes detrimental disease defects. Here, we assessed the enteric nervous system (ENS) of the mouse, nonhuman primate, and human by advanced 3D imaging. We observed the profound neurodegeneration of catecholaminergic axons in human colons with ulcerative colitis, and similarly, in mouse colons during acute dextran sulfate sodium-induced colitis. However, we unexpectedly revealed that blockage of such axonal degeneration by the Sarm1 deletion in mice exacerbated the colitis condition. In contrast, pharmacologic ablation or chemogenetic inhibition of catecholaminergic axons suppressed the colon inflammation. We further showed that the catecholaminergic neurotransmitter norepinephrine exerted a pro-inflammatory function by enhancing the expression of IL-17 cytokines. Together, this study demonstrated that Sarm1-mediated neurodegeneration within the ENS mitigated local inflammation of the colon, uncovering a previously-unrecognized beneficial role of axonal degeneration in this disease context.