2022 Vol. 13, No. 10

Understanding the regulatory networks for germ cell fate specification is necessary to developing strategies for improving the efficiency of germ cell production in vitro. Shi et al. developed a coupled screening strategy that took advantage of an arrayed BiFC platform for protein-protein interaction screens and EpiLC-induction assays using reporter mESCs. Investigation of candidate interaction partners of core human pluripotent factors OCT4, NANOG, KLF4 and SOX2 in EpiLC differentiation assays identified novel primordial germ cell (PGC)-inducing factors including BEN-domain (BEND/ Bend) family members. Through RNA-seq, ChIP-seq, and ATAC-seq analyses, the authors showed that Bend5 worked together with Bend4 and helped mark chromatin boundaries to promote EpiLC induction in vitro. These suggest that BEND/Bend proteins represent a new family of transcriptional modulators and chromatin boundary factors that participate in gene expression regulation during early germline development.

Recollection
Darwinian rebel: The legacy of Loh-Seng Tsai—Chinese animal psychologist
Yong Wang, Wei Chen, Shiying Li, Bin Yin
2022, 13(10): 701-706. doi: 10.1007/s13238-021-00849-4
Abstract:
Review
New pathogenic insights from large animal models of neurodegenerative diseases
Peng Yin, Shihua Li, Xiao-Jiang Li, Weili Yang
2022, 13(10): 707-720. doi: 10.1007/s13238-022-00912-8
Abstract:
Animal models are essential for investigating the pathogenesis and developing the treatment of human diseases. Identification of genetic mutations responsible for neurodegenerative diseases has enabled the creation of a large number of small animal models that mimic genetic defects found in the affected individuals. Of the current animal models, rodents with genetic modifications are the most commonly used animal models and provided important insights into pathogenesis. However, most of genetically modified rodent models lack overt neurodegeneration, imposing challenges and obstacles in utilizing them to rigorously test the therapeutic effects on neurodegeneration. Recent studies that used CRISPR/Cas9-targeted large animal (pigs and monkeys) have uncovered important pathological events that resemble neurodegeneration in the patient's brain but could not be produced in small animal models. Here we highlight the unique nature of large animals to model neurodegenerative diseases as well as the limitations and challenges in establishing large animal models of neurodegenerative diseases, with focus on Huntington disease, Amyotrophic lateral sclerosis, and Parkinson diseases. We also discuss how to use the important pathogenic insights from large animal models to make rodent models more capable of recapitulating important pathological features of neurodegenerative diseases.
Research Articles
Bend family proteins mark chromatin boundaries and synergistically promote early germ cell differentiation
Guang Shi, Yaofu Bai, Xiya Zhang, Junfeng Su, Junjie Pang, Quanyuan He, Pengguihang Zeng, Junjun Ding, Yuanyan Xiong, Jingran Zhang, Jingwen Wang, Dan Liu, Wenbin Ma, Junjiu Huang, Zhou Songyang
2022, 13(10): 721-741. doi: 10.1007/s13238-021-00884-1
Abstract:
Understanding the regulatory networks for germ cell fate specification is necessary to developing strategies for improving the efficiency of germ cell production in vitro. In this study, we developed a coupled screening strategy that took advantage of an arrayed bi-molecular fluorescence complementation (BiFC) platform for protein-protein interaction screens and epiblast-like cell (EpiLC)-induction assays using reporter mouse embryonic stem cells (mESCs). Investigation of candidate interaction partners of core human pluripotent factors OCT4, NANOG, KLF4 and SOX2 in EpiLC differentiation assays identified novel primordial germ cell (PGC)-inducing factors including BEN-domain (BEND/Bend) family members. Through RNA-seq, ChIP-seq, and ATAC-seq analyses, we showed that Bend5 worked together with Bend4 and helped mark chromatin boundaries to promote EpiLC induction in vitro. Our findings suggest that BEND/Bend proteins represent a new family of transcriptional modulators and chromatin boundary factors that participate in gene expression regulation during early germline development.
Unveiling E2F4, TEAD1 and AP-1 as regulatory transcription factors of the replicative senescence program by multi-omics analysis
Yuting Wang, Liping Liu, Yifan Song, Xiaojie Yu, Hongkui Deng
2022, 13(10): 742-759. doi: 10.1007/s13238-021-00894-z
Abstract:
Senescence, a stable state of growth arrest, affects many physiological and pathophysiological processes, especially aging. Previous work has indicated that transcription factors (TFs) play a role in regulating senescence. However, a systematic study of regulatory TFs during replicative senescence (RS) using multi-omics analysis is still lacking. Here, we generated time-resolved RNA-seq, reduced representation bisulfite sequencing (RRBS) and ATAC-seq datasets during RS of mouse skin fibroblasts, which demonstrated that an enhanced inflammatory response and reduced proliferative capacity were the main characteristics of RS in both the transcriptome and epigenome. Through integrative analysis and genetic manipulations, we found that transcription factors E2F4, TEAD1 and AP-1 are key regulators of RS. Overexpression of E2f4 improved cellular proliferative capacity, attenuated SA-β-Gal activity and changed RS-associated differentially methylated sites (DMSs). Moreover, knockdown of Tead1 attenuated SA-β-Gal activity and partially altered the RS-associated transcriptome. In addition, knockdown of Atf3, one member of AP-1 superfamily TFs, reduced Cdkn2a (p16) expression in pre-senescent fibroblasts. Taken together, the results of this study identified transcription factors regulating the senescence program through multi-omics analysis, providing potential therapeutic targets for anti-aging.
8 Å structure of the outer rings of the Xenopus laevis nuclear pore complex obtained by cryo-EM and AI
Linhua Tai, Yun Zhu, He Ren, Xiaojun Huang, Chuanmao Zhang, Fei Sun
2022, 13(10): 760-777. doi: 10.1007/s13238-021-00895-y
Abstract:
The nuclear pore complex (NPC), one of the largest protein complexes in eukaryotes, serves as a physical gate to regulate nucleocytoplasmic transport. Here, we determined the 8 Å resolution cryo-electron microscopic (cryo-EM) structure of the outer rings containing nuclear ring (NR) and cytoplasmic ring (CR) from the Xenopus laevis NPC, with local resolutions reaching 4.9 Å. With the aid of AlphaFold2, we managed to build a pseudoatomic model of the outer rings, including the Y complexes and flanking components. In this most comprehensive and accurate model of outer rings to date, the almost complete Y complex structure exhibits much tighter interaction in the hub region. In addition to two copies of Y complexes, each asymmetric subunit in CR contains five copies of Nup358, two copies of the Nup214 complex, two copies of Nup205 and one copy of newly identified Nup93, while that in NR contains one copy of Nup205, one copy of ELYS and one copy of Nup93. These in-depth structural features represent a great advance in understanding the assembly of NPCs.
Correction
Correction to: Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2
Rui Xiong, Leike Zhang, Shiliang Li, Yuan Sun, Minyi Ding, Yong Wang, Yongliang Zhao, Yan Wu, Weijuan Shang, Xiaming Jiang, Jiwei Shan, Zihao Shen, Yi Tong, Liuxin Xu, Yu Chen, Yingle Liu, Gang Zou, Dimitri Lavillette, Zhenjiang Zhao, Rui Wang, Lili Zhu, Gengfu Xiao, Ke Lan, Honglin Li, Ke Xu
2022, 13(10): 778-778. doi: 10.1007/s13238-020-00801-y
Abstract: