Journal of Genetics and Genomics

Engineering T cells for immunotherapy of primary human hepatocellular carcinoma

Leidy D. Caraballo Galva, Lun Cai, Yanxia Shao, Yukai He

2020, 47(1): 1-15. doi: 10.1016/j.jgg.2020.01.002

Abstract (138) HTML PDF (3)

Abstract:
Liver cancers, majority of which are primary hepatocellular carcinoma (HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4^th most common cause of male cancer deaths. Novel therapies are urgently needed. Over the last few years, immunotherapies, especially the checkpoint blockades and adoptive cell therapies of engineered T cells, have demonstrated a great potential for treating malignant tumors including HCC. In this review, we summarize the current ongoing research of antigen-specific immunotherapies including cancer vaccines and adoptive cell therapies for HCC. We briefly discuss the HCC cancer vaccine and then focus on the antigen-specific T cells genetically engineered with the T cell receptor genes (TCRTs) and the chimeric antigen receptor genes (CARTs). We first review the current options of TCRTs and CARTs immunotherapies for HCC, and then analyze the factors and parameters that may help to improve the design of TCRTs and CARTs to enhance their antitumor efficacy and safety. Our goals are to render readers a panoramic view of the current stand of HCC immunotherapies and provide some strategies to design better TCRTs and CARTs to achieve more effective and durable antitumor effects.

Molecular feature and therapeutic perspectives of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

Qianru Huang, Xu Liu, Yujia Zhang, Jingyao Huang, Dan Li, Bin Li

2020, 47(1): 17-26. doi: 10.1016/j.jgg.2019.11.011

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Abstract:
Regulatory T (Treg) cells, a subtype of immunosuppressive CD4⁺ T cells, are vital for maintaining immune homeostasis in healthy people. Forkhead box protein P3 (FOXP3), a member of the forkhead-winged-helix family, is the pivotal transcriptional factor of Treg cells. The expression, post-translational modifications, and protein complex of FOXP3 present a great impact on the functional stability and immune plasticity of Treg cells in vivo. In particular, the mutation of FOXP3 can result in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, which is a rare genetic disease mostly diagnosed in early childhood and can soon be fatal. IPEX syndrome is related to several manifestations, including dermatitis, enteropathy, type 1 diabetes, thyroiditis, and so on. Here, we summarize some recent findings on FOXP3 regulation and Treg cell function. We also review the current knowledge about the underlying mechanism of FOXP3 mutant-induced IPEX syndrome and some latest clinical prospects. At last, this review offers a novel insight into the role played by the FOXP3 complex in potential therapeutic applications in IPEX syndrome.

Structural and immunogenomic insights into B-cell receptor activation

Yangyang Feng, Yu Wang, Shaocun Zhang, Kabeer Haneef, Wanli Liu

2020, 47(1): 27-35. doi: 10.1016/j.jgg.2019.12.003

Abstract (70) HTML PDF (3)

Abstract:
B cells express B-cell receptors (BCRs) which recognize antigen to trigger signaling cascades for B-cell activation and subsequent antibody production. BCR activation has a crucial influence on B-cell fate. How BCR is activated upon encountering antigen remains to be solved, although tremendous progresses have been achieved in the past few years. Here, we summarize the models that have been proposed to explain BCR activation, including the cross-linking model, the conformation-induced oligomerization model, the dissociation activation model, and the conformational change model. Especially, we elucidate the partially resolved structures of antibodies and/or BCRs by far and discusse how these current structural and further immunogenomic messages and more importantly the future studies may shed light on the explanation of BCR activation and the relevant diseases in the case of dysregulation.

Efficient generation of zebrafish maternal-zygotic mutants through transplantation of ectopically induced and Cas9/gRNA targeted primordial germ cells

Fenghua Zhang, Xianmei Li, Mudan He, Ding Ye, Feng Xiong, Golpour Amin, Zuoyan Zhu, Yonghua Sun

2020, 47(1): 37-47. doi: 10.1016/j.jgg.2019.12.004

Abstract (101) HTML PDF (3)

Abstract:
The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology has been widely utilized for knocking out genes involved in various biological processes in zebrafish. Despite this technology is efficient for generating different mutations, one of the main drawbacks is low survival rate during embryogenesis when knocking out some embryonic lethal genes. To overcome this problem, we developed a novel strategy using a combination of CRISPR/Cas9 mediated gene knockout with primordial germ cell (PGC) transplantation (PGCT) to facilitate and speed up the process of zebrafish mutant generation, particularly for embryonic lethal genes. Firstly, we optimized the procedure for CRISPR/Cas9 targeted PGCT by increasing the efficiencies of genome mutation in PGCs and induction of PGC fates in donor embryos for PGCT. Secondly, the optimized CRISPR/Cas9 targeted PGCT was utilized for generation of maternal-zygotic (MZ) mutants oftcf7l1a (gene essential for head development), pou5f3 (gene essential for zygotic genome activation) and chd (gene essential for dorsal development) at F₁ generation with relatively high efficiency. Finally, we revealed some novel phenotypes in MZ mutants of tcf7l1a and chd, as MZtcf7l1a showed elevated neural crest development while MZchd had much severer ventralization than its zygotic counterparts. Therefore, this study presents an efficient and powerful method for generating MZ mutants of embryonic lethal genes in zebrafish. It is also feasible to speed up the genome editing in commercial fishes by utilizing a similar approach by surrogate production of CRISPR/Cas9 targeted germ cells.

Genome-wide evolution analysis reveals low CpG contents of fast-evolving genes and identifies antiviral microRNAs

Wenhong Zu, Hang Zhang, Xun Lan, Xu Tan

2020, 47(1): 49-60. doi: 10.1016/j.jgg.2019.12.001

Abstract (84) HTML PDF (2)

Abstract:
Noncoding RNAs (ncRNAs) play important roles in many biological processes and provide materials for evolutionary adaptations beyond protein-coding genes, such as in the arms race between the host and pathogen. However, currently, a comprehensive high-resolution analysis of primate genomes that includes the latest annotated ncRNAs is not available. Here, we developed a computational pipeline to estimate the selections that act on noncoding regions based on comparisons with a large number of reference sequences in introns adjacent to the interested regions. Our method yields result comparable with those of the established codon-based method and phyloP method for coding genes; thus, it provides a holistic framework for estimating the selection on the entire genome. We further showed that fast-evolving protein-coding genes and their corresponding 5′ UTRs have a significantly lower frequency of the CpG dinucleotides than those evolving at an average pace, and these fast-evolving genes are enriched in the process of immunity and host defense. We also identified fast-evolving miRNAs with antiviral functions in cells. Our results provide a resource for high-resolution evolution analysis of the primate genomes.

Arabidopsis EED1 encoding a plant-specific nuclear protein is essential for early embryogenesis

Mai Yang, Chun Yan, Megan Griffith, Jinping Zhao, Yongbiao Zhang, Daoxin Xie, Jianbin Yan

2020, 47(1): 61-64. doi: 10.1016/j.jgg.2019.12.005

Abstract (117) HTML PDF (6)

Abstract:

Rapid and specific isolation of intact mitochondria from Arabidopsis leaves

Lilan Luo, Yajun He, Qian Xu, Wenhui Lyu, Jijun Yan, Peiyong Xin, Dahan Zhang, Jinfang Chu, Jiayang Li, Hong Yu

2020, 47(1): 65-68. doi: 10.1016/j.jgg.2020.01.001

Abstract (86) HTML PDF (3)

Abstract:

2020 Vol. 47, No. 1