Journal of Genetics and Genomics

Current status and perspectives of regulatory T cell-based therapy

Guojun Qu, Jieqiong Chen, Yangyang Li, Yaqin Yuan, Rui Liang, Bin Li

2022, 49(7): 599-611. doi: 10.1016/j.jgg.2022.05.005

Abstract (388) PDF (90)

Abstract:
The CD4⁺FOXP3⁺ regulatory T (Treg) cells are essential for maintaining immune homeostasis in healthy individuals. Results from clinical trials of Treg cell-based therapies in patients with graft versus host disease (GVHD), type 1 diabetes (T1D), liver transplantation, and kidney transplantation have demonstrated that adoptive transfer of Treg cells is emerging as a promising strategy to promote immune tolerance. Here we provide an overview of recent progresses and current challenges of Treg cell-based therapies. We summarize the completed and ongoing clinical trials with human Treg cells. Notably, a few of the chimeric antigen receptor (CAR)-Treg cell therapies are currently undergoing clinical trials. Meanwhile, we describe the new strategies for engineering Treg cells used in preclinical studies. Finally, we envision that the use of novel synthetic receptors, metabolic regulators, combined therapies, and in vivo generated antigen-specific or engineered Treg cells through the delivery of modified mRNA and CRISPR-based gene editing will further promote the advances of next-generation Treg cell therapies.

Mesenteric lymph system constitutes the second route in gut-liver axis and transports metabolism-modulating gut microbial metabolites

Ying Yu, Bin Liu, Xiaolin Liu, Xuan Zhang, Wenhui Zhang, He Tian, Guanghou Shui, Wenzhao Wang, Moshi Song, Jun Wang

2022, 49(7): 612-623. doi: 10.1016/j.jgg.2022.03.012

Abstract (1337) PDF (154)

Abstract:
The gut–liver axis denotes the intricate connection and interaction between gut microbiome and liver, in which compositional and functional shifts in gut microbiome affect host metabolism. Hepatic portal vein of the blood circulation system has been thought to be the major route for metabolite transportation in the gut–liver axis, but the existence and importance of other routes remain elusive. Here, we perform metabolome comparison in blood circulation and mesenteric lymph systems and identify significantly shifted metabolites in serum and mesentery. Using cellular assays, we find that the majority of decreased metabolites in lymph system under high-fat diet are effective in alleviating metabolic disorders, indicating a high potential of lymph system in regulating liver metabolism. Among those, a representative metabolite, L-carnitine, reduces diet-induced obesity in mice. Metabolic tracing analysis identifies that L-carnitine is independently transported by the mesenteric lymph system, serving as an example that lymph circulation comprises a second route in the gut–liver axis to modulate liver metabolism. Our study provides new insights into metabolite transportation via mesenteric lymph system in the gut–liver axis, offers an extended scope for the investigations in host-gut microbiota metabolic interactions and potentially new targets in the treatment of metabolic disorders.

Reproductive tissue-specific translatome of a rice thermo-sensitive genic male sterile line

Wei Liu, Jing Sun, Ji Li, Chunyan Liu, Fuyan Si, Bin Yan, Zhen Wang, Xianwei Song, Yuanzhu Yang, Yuxian Zhu, Xiaofeng Cao

2022, 49(7): 624-635. doi: 10.1016/j.jgg.2022.01.002

Abstract (288) PDF (132)

Abstract:
Translational regulation, especially tissue- or cell type-specific gene regulation, plays essential roles in plant growth and development. Thermo-sensitive genic male sterile (TGMS) lines have been widely used for hybrid breeding in rice (Oryza sativa). However, little is known about translational regulation during reproductive stage in TGMS rice. Here, we use translating ribosome affinity purification (TRAP) combined with RNA sequencing to investigate the reproductive tissue-specific translatome of TGMS rice expressing FLAG-tagged ribosomal protein L18 (RPL18) from the germline-specific promoter MEIOSIS ARRESTED AT LEPTOTENE1 (MEL1). Differentially expressed genes at the transcriptional and translational levels are enriched in pollen and anther-related formation and development processes. These contain a number of genes reported to be involved in tapetum programmed cell death (PCD) and lipid metabolism during pollen development and anther dehiscence in rice, including several encoding transcription factors and key enzymes, as well as several long non-coding RNAs (lncRNAs) that potentially affect tapetum and pollen-related genes in male sterility. This study represents the comprehensive reproductive tissue-specific characterization of the translatome in TGMS rice. These results contribute to our understanding of the molecular basis of sterility in TGMS rice and will facilitate further genetic manipulation of TGMS rice in two-line breeding systems.

The sex determination gene doublesex regulates expression and secretion of the basement membrane protein Collagen IV

Qionglin Peng, Jiangtao Chen, Rong Wang, Huan Zhu, Caihong Han, Xiaoxiao Ji, Yufeng Pan

2022, 49(7): 636-644. doi: 10.1016/j.jgg.2021.12.010

Abstract (264) PDF (98)

Abstract:
The highly conserved doublesex (dsx) and doublesex/mab-3 related (Dmrt) genes control sexually dimorphic traits across animals. The dsx gene encodes sex-specific transcription factors, Dsx^M in males and Dsx^F in females, which function differentially and often oppositely to establish sexual dimorphism. Here, we report that mutations in dsx, or overexpression of dsx, result in abnormal distribution of the basement membrane (BM) protein Collagen IV in the fat body. We find that Dsx isoforms regulate the expression of Collagen IV in the fat body and its secretion into the BM of other tissues. We identify the procollagen lysyl hydroxylase (dPlod) gene, which is involved in the biosynthesis of Collagen IV, as a direct target of Dsx. We further show that Dsx regulates Collagen IV through dPlod-dependent and independent pathways. These findings reveal how Dsx isoforms function in the secretory fat body to regulate Collagen IV and remotely establish sexual dimorphism.

Characteristics of TP53 germline variants and their correlations with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome in Chinese tumor patients

Panwen Tian, Xiaoyan Zhang, Sheng Yang, Yu Fang, Hongling Yuan, Wei Li, Honglin Zhu, Fangping Zhao, Jinlei Ding, Yunshu Zhu, Sizhen Wang, Guochen Sun, Hongbin Ni, Tonghui Ma, Ting Lei

2022, 49(7): 645-653. doi: 10.1016/j.jgg.2021.12.012

Abstract (240) PDF (103)

Abstract:
Li-Fraumeni syndrome (LFS), a rare autosomal-dominant inheritance condition, is associated with a family cancer history as well as pathogenic/likely-pathogenic TP53 germline variants (P/LP TP53 GV). The current clinical methods for detecting LFS are limited. Here, we retrospectively investigate P/LP TP53 GV among Chinese cancer patients by next-generation sequencing and evaluate its relationship with a family cancer history. A total of 270 out of 19,226 cancer patients have TP53 GV, including 53 patients with P/LP TP53 GV. Patients with P/LP TP53 GV are mainly found in male with glioma, lung cancer or sarcoma. The median age of diagnosis for P/LP TP53 GV patients is significantly lower than that of non-P/LP TP53 GV patients (31-years vs. 53-years; P < 0.01). One LFS patient and 3 Li-Fraumeni-like syndrome (LFL) patients are among the 26 followed-up P/LP TP53 GV patients. Among 25 types of P/LP TP53 GV, the highest variant frequencies occurred at codon 175 and 248. p.M237I, p.R158H, p.C238Y and p.C275R, are firstly identified among the Chinese LFS/LFL patients. This study reports the (P/LP) TP53 GV characteristics of Chinese pan-cancer patients. These findings suggest analyzing the P/LP TP53 GV in cancer patients is an effective strategy for identifying cancer predisposition syndrome.

Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage

Elisabetta Morini, Dadi Gao, Emily M. Logan, Monica Salani, Aram J. Krauson, Anil Chekuri, Yei-Tsung Chen, Ashok Ragavendran, Probir Chakravarty, Serkan Erdin, Alexei Stortchevoi, Jesper Q. Svejstrup, Michael E. Talkowski, Susan A. Slaugenhaupt

2022, 49(7): 654-665. doi: 10.1016/j.jgg.2021.11.011

Abstract (275) PDF (91)

Abstract:
Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1 (ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse (Elp1) and observed that human ELP1 expression rescues embryonic development in a dose-dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of ELP1. We found that ELP1 is essential for the expression of genes responsible for nervous system development. Further, gene length analysis of the differentially expressed genes showed that the loss of Elp1 mainly impacts the expression of long genes and that by gradually restoring Elongator, their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on ELP1 expression.

The transcription factor Sox30 is involved in Nile tilapia spermatogenesis

Ling Wei, Yaohao Tang, Xianhai Zeng, Yueqin Li, Song Zhang, Li Deng, Lingsong Wang, Deshou Wang

2022, 49(7): 666-676. doi: 10.1016/j.jgg.2021.11.003

Abstract (235) PDF (99)

Abstract:
Spermatogenesis is a complex process in which spermatogonial stem cells differentiate and develop into mature spermatozoa. The transcriptional regulatory network involved in fish spermatogenesis remains poorly understood. Here, we demonstrate in Nile tilapia that the Sox transcription factor family member Sox30 is specifically expressed in the testes and mainly localizes to spermatocytes and spermatids. CRISPR/Cas9-mediated sox30 mutation results in abnormal spermiogenesis, reduction of sperm motility, and male subfertility. Comparative transcriptome analysis shows that sox30 mutation alters the expression of genes involved in spermatogenesis. Further chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), ChIP-PCR, and luciferase reporter assays revealed that Sox30 positively regulates the transcription of ift140 and ptprb, two genes involved in spermiogenesis, by directly binding to their promoters. Our data, taken together, indicate that Sox30 plays an essential role in Nile tilapia spermatogenesis by directly regulating the transcription of the spermiogenesis-related genes ift140 and ptprb.

Cryo-EM structure of R-loop monoclonal antibody S9.6 in recognizing RNA: DNA hybrids

Qin Li, Chao Lin, Zhipu Luo, Haitao Li, Xueming Li, Qianwen Sun

2022, 49(7): 677-680. doi: 10.1016/j.jgg.2022.04.011

Abstract (335) PDF (92)

Abstract:

DRBin: metagenomic binning based on deep representation learning

Gang Mao, Yulin Wu, Yang Zhang, Xuan Wang, Yan Zhu, Bo Liu, Yadong Wang, Junyi Li

2022, 49(7): 681-684. doi: 10.1016/j.jgg.2021.12.005

Abstract (213) PDF (20)

Abstract:

Comprehensive understanding to the public health risk of environmental microbes via a microbiome-based index

Zheng Sun, Xudong Liu, Gongchao Jing, Yuzhu Chen, Shuaiming Jiang, Meng Zhang, Jiquan Liu, Jian Xu, Xiaoquan Su

2022, 49(7): 685-688. doi: 10.1016/j.jgg.2021.12.011

Abstract (590) PDF (184)

Abstract:

CDCP: a visualization and analyzing platform for single-cell datasets

Yuejiao Li, Tao Yang, Tingting Lai, Lijin You, Fan Yang, Jiaying Qiu, Lina Wang, Wensi Du, Cong Hua, Zhicheng Xu, Jia Cai, Zhiyong Li, Yiqun Liu, Ling Li, Minwen Zhang, Jing Chen, Lei Zhang, Dongsheng Chen, Weiwen Wang, Shiping Liu, Liang Wu, Wenjun Zeng, Bo Wang, Xiaofeng Wei, Longqi Liu, Fengzhen Chen

2022, 49(7): 689-692. doi: 10.1016/j.jgg.2021.12.004

Abstract (385) PDF (116)

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2022 Vol. 49, No. 7