2020 Vol. 11, No. 7

Epigenetic modifications, including those on DNA andhistones, have been shown to regulate cellular metabolismby controlling expression of enzymes involved in thecorresponding metabolic pathways. In turn, metabolic fluxinfluences epigenetic regulation by affecting the biosyntheticbalance of enzyme cofactors or donors for certainchromatin modifications. Recently, non-enzymatic covalentmodifications (NECMs) by chemically reactive metaboliteshave been reported to manipulate chromatin architectureand gene transcription through multiple mechanisms. Here,we summarize recent advances in the identification andcharacterization of NECMs on nucleic acids, histones, andtranscription factors, providing an additional mechanistic linkbetween metabolism and epigenetics.
Chi-Nan Hu-Pioneer of Chinese neuroscience and cognitive science
Yunjin Wang, Yanyan Qian
2020, 11(7): 465-468. doi: 10.1007/s13238-019-00658-w
SIRT7 slows down stem cell aging by preserving heterochromatin: a perspective on the new discovery
Luyang Sun, Weiwei Dang
2020, 11(7): 469-471. doi: 10.1007/s13238-020-00735-5
HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma
Xiaoguang Wang, Brittany C. Waschke, Rachel A Woolaver, Samantha M. Y. Chen, Zhangguo Chen, Jing H. Wang
2020, 11(7): 472-482. doi: 10.1007/s13238-020-00694-x
Immunotherapy has been applied successfully to treat B-cell lymphomas in preclinical models or clinical settings. However, immunotherapy resistance is a major challenge for B-cell lymphoma treatment. To overcome this issue, combinatorial therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas. One of such strategies is to combine immunotherapy with histone deacetylase (HDAC) inhibitors. HDAC inhibitors can potentially increase tumor immunogenicity, promote anti-tumor immune responses, or reverse immunosuppressive tumor environments. Thus, the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment. However, not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target. Hence, we suggest that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors. Here, we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.
Research articles
SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer
Shijia Bi, Zunpeng Liu, Zeming Wu, Zehua Wang, Xiaoqian Liu, Si Wang, Jie Ren, Yan Yao, Weiqi Zhang, Moshi Song, Guang-Hui Liu, Jing Qu
2020, 11(7): 483-504. doi: 10.1007/s13238-020-00728-4
SIRT7, a sirtuin family member implicated in aging and disease, is a regulator of metabolism and stress responses. It remains elusive how human somatic stem cell populations might be impacted by SIRT7. Here, we found that SIRT7 expression declines during human mesenchymal stem cell (hMSC) aging and that SIRT7 deficiency accelerates senescence. Mechanistically, SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins, thus maintaining the repressive state of heterochromatin at nuclear periphery. Accordingly, deficiency of SIRT7 results in loss of heterochromatin, de-repression of the LINE1 retrotransposon (LINE1), and activation of innate immune signaling via the cGAS-STING pathway. These agingassociated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor. Together, these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.
Cryo-EM snapshots of mycobacterial arabinosyltransferase complex EmbB2-AcpM2
Lu Zhang, Yao Zhao, Ruogu Gao, Jun Li, Xiuna Yang, Yan Gao, Wei Zhao, Sudagar S. Gurcha, Natacha Veerapen, Sarah M. Batt, Kajelle Kaur Besra, Wenqing Xu, Lijun Bi, Xian'en Zhang, Luke W. Guddat, Haitao Yang, Quan Wang, Gurdyal S. Besra, Zihe Rao
2020, 11(7): 505-517. doi: 10.1007/s13238-020-00726-6
Inhibition of Mycobacterium tuberculosis (Mtb) cell wall assembly is an established strategy for anti-TB chemotherapy. Arabinosyltransferase EmbB, which catalyzes the transfer of arabinose from the donor decaprenyl-phosphate-arabinose (DPA) to its arabinosyl acceptor is an essential enzyme for Mtb cell wall synthesis. Analysis of drug resistance mutations suggests that EmbB is the main target of the front-line anti-TB drug, ethambutol. Herein, we report the cryo-EM structures of Mycobacterium smegmatis EmbB in its "resting state" and DPA-bound "active state". EmbB is a fifteentransmembrane-spanning protein, assembled as a dimer. Each protomer has an associated acyl-carrierprotein (AcpM) on their cytoplasmic surface. Conformational changes upon DPA binding indicate an asymmetric movement within the EmbB dimer during catalysis. Functional studies have identified critical residues in substrate recognition and catalysis, and demonstrated that ethambutol inhibits transferase activity of EmbB by competing with DPA. The structures represent the first step directed towards a rational approach for anti-TB drug discovery.
Modulation of metabolic functions through Cas13d-mediated gene knockdown in liver
Bingbing He, Wenbo Peng, Jia Huang, Hang Zhang, Yingsi Zhou, Xiali Yang, Jing Liu, Zhijie Li, Chunlong Xu, Mingxing Xue, Hui Yang, Pengyu Huang
2020, 11(7): 518-524. doi: 10.1007/s13238-020-00700-2
Human cytomegalovirus DNA and immediate early protein 1/2 are highly associated with glioma and prognosis
Le Wen, Fei Zhao, Yong Qiu, Shuang Cheng, Jin-Yan Sun, Wei Fang, Simon Rayner, Michael A. McVoy, Xing-Jun Jiang, Qiyi Tang, Fang-Cheng Li, Fei Hu, Min-Hua Luo
2020, 11(7): 525-533. doi: 10.1007/s13238-020-00696-9
FAK-targeting PROTAC as a chemical tool for the investigation of non-enzymatic FAK function in mice
Hongying Gao, Chunwei Zheng, Jian Du, Yue Wu, Yonghui Sun, Chunsheng Han, Kehkooi Kee, Yu Rao
2020, 11(7): 534-539. doi: 10.1007/s13238-020-00732-8
Correction to: Characterization of oogonia stem cells in mice by Fragilis
Xiaoyan Sheng, Chenglei Tian, Linlin Liu, Lingling Wang, Xiaoying Ye, Jie Li, Ming Zeng, Lin Liu
2020, 11(7): 540-541. doi: 10.1007/s13238-019-00675-9