Journal of Genetics and Genomics

Another piece of puzzle for the human microbiome: the gut virome under dietary modulation

Fengxiang Zhao, Jinfeng Wang

2024, 51(10): 983-996. doi: 10.1016/j.jgg.2024.04.013

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Abstract:
The virome is the most abundant and highly variable microbial consortium in the gut. Because of difficulties in isolating and culturing gut viruses and the lack of reference genomes, the virome has remained a relatively elusive aspect of the human microbiome. In recent years, studies on the virome have accumulated growing evidence showing that the virome is diet-modulated and widely involved in regulating health. Here, we review the responses of the gut virome to dietary intake and the potential health implications, presenting changes in the gut viral community and preferences of viral members to particular diets. We further discuss how viral-bacterial interactions and phage lifestyle shifts shape the gut microbiota. We also discuss the specific functions conferred by diet on the gut virome and bacterial community in the context of horizontal gene transfer, as well as the import of new viral members along with the diet. Collating these studies will expand our understanding of the dietary regulation of the gut virome and inspire dietary interventions and health maintenance strategies targeting the gut microbiota.

A positive feedback loop between PLD1 and NF-κB signaling promotes tumorigenesis of nasopharyngeal carcinoma

Ya-Qing Zhou, Xi-Xi Cheng, Shuai He, Shu-Qiang Liu, Yi-Qi Li, Pan-Pan Wei, Chun-Ling Luo, Jin-Xin Bei

2024, 51(10): 997-1006. doi: 10.1016/j.jgg.2024.06.004

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Phospholipase D (PLD) lipid-signaling enzyme superfamily has been widely implicated in various human malignancies, but its role and underlying mechanism remain unclear in nasopharyngeal carcinoma (NPC). Here, we analyze the expressions of 6 PLD family members between 87 NPC and 10 control samples through transcriptome analysis. Our findings reveal a notable upregulation of PLD1 in both NPC tumors and cell lines, correlating with worse disease-free and overall survival in NPC patients. Functional assays further elucidate the oncogenic role of PLD1, demonstrating its pivotal promotion of critical tumorigenic processes such as cell proliferation and migration in vitro, as well as tumor growth in vivo. Notably, our study uncovers a positive feedback loop between PLD1 and the NF-κB signaling pathway to render NPC progression. Specifically, PLD1 enhances NF-κB activity by facilitating the phosphorylation and nuclear translocation of RELA, which in turn binds to the promoter of PLD1, augmenting its expression. Moreover, RELA overexpression markedly rescues the inhibitory effects in PLD1-depleted NPC cells. Importantly, the application of the PLD1 inhibitor, VU0155069, substantially inhibits NPC tumorigenesis in a patient-derived xenograft model. Together, our findings identify PLD1/NF-κB signaling as a positive feedback loop with promising therapeutic and prognostic potential in NPC.

Deficiency of MFSD6L, an acrosome membrane protein, causes oligoasthenoteratozoospermia in humans and mice

Dapeng Zhou, Huan Wu, Lingbo Wang, Xuemei Wang, Shuyan Tang, Yiling Zhou, Jiaxiong Wang, Bangguo Wu, Jianan Tang, Xuehai Zhou, Shixiong Tian, Shuang Liu, Mingrong Lv, Xiaojin He, Li Jin, Huijuan Shi, Feng Zhang, Yunxia Cao, Chunyu Liu

2024, 51(10): 1007-1019. doi: 10.1016/j.jgg.2024.06.008

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Oligoasthenoteratozoospermia is an important factor affecting male fertility and has been found to be associated with genetic factors. However, there are still a proportion of oligoasthenoteratozoospermia cases that cannot be explained by known pathogenic genetic variants. Here, we perform genetic analyses and identify bi-allelic loss-of-function variants of MFSD6L from an oligoasthenoteratozoospermia-affected family. Mfsd6l knock-out male mice also present male subfertility with reduced sperm concentration, motility, and deformed acrosomes. Further mechanistic analyses reveal that MFSD6L, as an acrosome membrane protein, plays an important role in the formation of acrosome by interacting with the inner acrosomal membrane protein SPACA1. Moreover, poor embryonic development is consistently observed after intracytoplasmic sperm injection treatment using spermatozoa from the MFSD6L-deficient man and male mice. Collectively, our findings reveal that MFSD6L is required for the anchoring of sperm acrosome and head shaping. The deficiency of MFSD6L affects male fertility and causes oligoasthenoteratozoospermia in humans and mice.

Ca²⁺-calpains axis regulates Yki stability and activity in Drosophila

Chaojun Zhai, Yunfeng Wang, Shenao Qi, Muhan Yang, Shian Wu

2024, 51(10): 1020-1029. doi: 10.1016/j.jgg.2024.04.011

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Yorkie (Yki) is a key effector of the Hippo pathway that activates the expression of targets by associating with the transcription factor Scalloped. Various upstream signals, such as cell polarity and mechanical cues, control transcriptional programs by regulating Yki activity. Searching for Yki regulatory factors has far-reaching significance for studying the Hippo pathway in development and human diseases. In this study, we identify Calpain-A (CalpA) and Calpain-B (CalpB), two calcium (Ca²⁺)-dependent modulatory proteases of the calpain family, as critical regulators of Yki in Drosophila that interact with Yki, respectively. Ca²⁺ induces Yki cleavage in a CalpA/CalpB-dependent manner, and the protease activity of CalpA/CalpB is pivotal for the cleavage. Furthermore, overexpression of CalpA or CalpB in Drosophila partially restores the large wing phenotype caused by Yki overexpression, and F98 of Yki is an important cleavage site by the Ca²⁺-calpains axis. Our study uncovers a unique mechanism whereby the Ca²⁺-calpain axis modulates Yki activity through protein cleavage.

The landscape and clinical relevance of intronic polyadenylation in human cancers

Xiaomeng Cheng, Guanghui Jiang, Xiaolan Zhou, Jing Wang, Zhaozhao Zhao, Jiayu Zhang, Ting Ni

2024, 51(10): 1030-1039. doi: 10.1016/j.jgg.2024.04.014

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Intronic polyadenylation (IPA) is an RNA 3′ end processing event which has been reported to play important roles in cancer development. However, the comprehensive landscape of IPA events across various cancer types is lacking. Here, we apply IPAFinder to identify and quantify IPA events in 10,383 samples covering all 33 cancer types from The Cancer Genome Atlas (TCGA) project. We identify a total of 21,835 IPA events, almost half of which are ubiquitously expressed. We identify 2761 unique dynamically changed IPA events across cancer types. Furthermore, we observe 8855 non-redundant clinically relevant IPA events, which could potentially be used as prognostic indicators. Our analysis also reveals that dynamic IPA usage within cancer signaling pathways may affect drug response. Finally, we develop a user-friendly data portal, IPACancer Atlas (http://www.tingni-lab.com/Pancan_IPA/), to search and explore IPAs in cancer.

miR-504 knockout regulates tumor cell proliferation and immune cell infiltration to accelerate oral cancer development

Xiaotang Wang, Xiaona Song, Yunhui Ma, Junting Yang, Jiping Gao, Tian Wang, Guoqiang Xu, Xiaoqi Chang, Shuxuan Shi, Rui Sun, Guohua Song

2024, 51(10): 1040-1054. doi: 10.1016/j.jgg.2024.06.002

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miR-504 plays a pivotal role in the progression of oral cancer. However, the underlying mechanism remains elusive in vivo. Here, we find that miR-504 is significantly down-regulated in oral cancer patients. We generate miR-504 knockout mice (miR-504^-/-) using CRISPR/Cas9 technology to investigate its impact on the malignant progression of oral cancer under exposure to 4-Nitroquinoline N-oxide (4NQO). We show that the deletion of miR-504 does not affect phenotypic characteristics, body weight, reproductive performance, and survival in mice, but results in changes in the blood physiological and biochemical indexes of the mice. Moreover, with 4NQO treatment, miR-504^-/- mice exhibit more pronounced pathological changes characteristic of oral cancer. RNA sequencing shows that the differentially expressed genes observed in samples from miR-504^-/- mice with oral cancer are involved in regulating cell metabolism, cytokine activation, and lipid metabolism-related pathways. Additionally, these differentially expressed genes are significantly enriched in lipid metabolism pathways that influence immune cell infiltration within the tumor microenvironment, thereby accelerating tumor development progression. Collectively, our results suggest that knockout of miR-504 accelerates malignant progression in 4NQO-induced oral cancer by regulating tumor cell proliferation and lipid metabolism, affecting immune cell infiltration.

GPR160 regulates the self-renewal and pluripotency of mouse embryonic stem cells via JAK1/STAT3 signaling pathway

Shasha Fan, Chuanliang Guo, Guanheng Yang, Lei Hong, Hongyu Li, Ji Ma, Yiye Zhou, Shuyue Fan, Yan Xue, Fanyi Zeng

2024, 51(10): 1055-1065. doi: 10.1016/j.jgg.2024.05.003

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G-protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and regulate various physiological and pathological processes. Despite extensive studies, the roles of GPCRs in mouse embryonic stem cells (mESCs) remain poorly understood. Here, we show that GPR160, a class A member of GPCRs, is dramatically downregulated concurrent with mESC differentiation into embryoid bodies in vitro. Knockdown of Gpr160 leads to downregulation of the expression of pluripotency-associated transcription factors and upregulation of the expression of lineage markers, accompanying with the arrest of the mESC cell-cycle in the G0/G1 phase. RNA-seq analysis shows that GPR160 participates in the JAK/STAT signaling pathway crucial for maintaining ESC stemness, and the knockdown of Gpr160 results in the downregulation of STAT3 phosphorylation level, which in turn is partially rescued by colivelin, a STAT3 activator. Consistent with these observations, GPR160 physically interacts with JAK1, and cooperates with leukemia inhibitory factor receptor (LIFR) and gp130 to activate the STAT3 pathway. In summary, our results suggest that GPR160 regulates mESC self-renewal and pluripotency by interacting with the JAK1-LIFR-gp130 complex to mediate the JAK1/STAT3 signaling pathway.

Lama1 upregulation prolongs the lifespan of the dy^H/dy^H mouse model of LAMA2-related congenital muscular dystrophy

Yidan Liu, Dandan Tan, Kaiyue Ma, Huaxia Luo, Jingping Mao, Jihang Luo, Qiang Shen, Luzheng Xu, Shiqi Yang, Lin Ge, Yuxuan Guo, Hong Zhang, Hui Xiong

2024, 51(10): 1066-1078. doi: 10.1016/j.jgg.2024.05.005

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LAMA2-related congenital muscular dystrophy (LAMA2-CMD), characterized by laminin-α2 deficiency, is debilitating and ultimately fatal. To date, no effective therapy has been clinically available. Laminin-α1, which shares significant similarities with laminin-α2, has been proven as a viable compensatory modifier. To evaluate its clinical applicability, we establish a Lama2 exon-3-deletion mouse model (dy^H/dy^H). The dy^H/dy^H mice exhibit early lethality and typical LAMA2-CMD phenotypes, allowing the evaluation of various endpoints. In dy^H/dy^H mice treated with synergistic activation mediator-based CRISPRa-mediated Lama1 upregulation, a nearly doubled median survival is observed, as well as improvements in weight and grip. Significant therapeutical effects are revealed by MRI, serum biochemical indices, and muscle pathology studies. Treating LAMA2-CMD with LAMA1 upregulation is feasible, and early intervention can alleviate symptoms and extend lifespan. Additionally, we reveal the limitations of LAMA1 upregulation, including high-dose mortality and non-sustained expression, which require further optimization in future studies.

S-acylation of YKT61 modulates its unconventional participation in the formation of SNARE complexes in Arabidopsis

Ting Ma, Jun-Ru Tan, Jin-Yu Lu, Sha Li, Yan Zhang

2024, 51(10): 1079-1088. doi: 10.1016/j.jgg.2024.04.007

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Hetero-tetrameric soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) complexes are critical for vesicle-target membrane fusion within the endomembrane system of eukaryotic cells. SNARE assembly involves four different SNARE motifs, Qa, Qb, Qc, and R, provided by three or four SNARE proteins. YKT6 is an atypical R-SNARE that lacks a transmembrane domain and is involved in multiple vesicle-target membrane fusions. Although YKT6 is evolutionarily conserved and essential, its function and regulation in different phyla seem distinct. Arabidopsis YKT61, the yeast and metazoan YKT6 homologue, is essential for gametophytic development, plays a critical role in sporophytic cells, and mediates multiple vesicle-target membrane fusion. However, its molecular regulation is unclear. We report here that YKT61 is S-acylated. Abolishing its S-acylation by a C195S mutation dissociates YKT61 from endomembrane structures and causes its functional loss. Although interacting with various SNARE proteins, YKT61 functions not as a canonical R-SNARE but coordinates with other R-SNAREs to participate in the formation of SNARE complexes. Phylum-specific molecular regulation of YKT6 may be evolved to allow more efficient SNARE assembly in different eukaryotic cells.

Dosage effect genes modulate grain development in synthesized Triticum durum-Haynaldia villosa allohexaploid

Zhongyu Yu, Baofeng Cui, Jin Xiao, Wu Jiao, Haiyan Wang, Zongkuan Wang, Li Sun, Qingxin Song, Jingya Yuan, Xiue Wang

2024, 51(10): 1089-1100. doi: 10.1016/j.jgg.2024.04.010

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Polyploidization in plants often leads to increased cell size and grain size, which may be affected by the increased genome dosage and transcription abundance. The synthesized Triticum durum (AABB)-Haynaldia villosa (VV) amphiploid (AABBVV) has significantly increased grain size, especially grain length, than the tetraploid and diploid parents. To investigate how polyploidization affects grain development at the transcriptional level, we perform transcriptome analysis using the immature seeds of T. durum, H. villosa, and the amphiploid. The dosage effect genes are contributed more by differentially expressed genes from genome V of H. villosa. The dosage effect genes overrepresent grain development-related genes. Interestingly, the vernalization gene TaVRN1 is among the positive dosage effect genes in the T. durum-H. villosa and T. turgidum-Ae. tauschii amphiploids. The expression levels of TaVRN1 homologs are positively correlated with the grain size and weight. The TaVRN1-B1 or TaVRN1-D1 mutation shows delayed florescence, decreased cell size, grain size, and grain yield. These data indicate that dosage effect genes could be one of the important explanations for increased grain size by regulating grain development. The identification and functional validation of dosage effect genes may facilitate the finding of valuable genes for improving wheat yield.

Genome-editing of a circadian clock gene TaPRR95 facilitates wheat peduncle growth and heading date

Mingxue Fu, Shaoshuai Liu, Yuqing Che, Dada Cui, Zhongyin Deng, Yang Li, Xinyu Zou, Xingchen Kong, Guoliang Chen, Min Zhang, Yifan Liu, Xiang Wang, Wei Liu, Danmei Liu, Shuaifeng Geng, Aili Li, Long Mao

2024, 51(10): 1101-1110. doi: 10.1016/j.jgg.2024.05.011

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Plant height and heading date are important agronomic traits in wheat (Triticum aestivum L.) that affect final grain yield. In wheat, knowledge of pseudo-response regulator (PRR) genes on agronomic traits is limited. Here, we identify a wheat TaPRR95 gene by genome-wide association studies to be associated with plant height. Triple allele mutant plants produced by CRISPR/Cas9 show increased plant height, particularly the peduncle, with an earlier heading date. The longer peduncle is mainly caused by the increased cell elongation at its upper section, whilst the early heading date is accompanied by elevated expression of flowering genes, such as TaFT and TaCO1. A peduncle-specific transcriptome analysis reveals up-regulated photosynthesis genes and down-regulated IAA/Aux genes for auxin signaling in prr95 plants that may act as a regulatory mechanism to promote robust plant growth. A haplotype analysis identifies a TaPRR95-B haplotype (Hap2) to be closely associated with reduced plant height and increased thousand-grain weight. Moreover, the Hap2 frequency is higher in cultivars than that in landraces, suggesting the artificial selection on the allele during wheat breeding. These findings suggest that TaPRR95 is a regulator for plant height and heading date, thereby providing an important target for wheat yield improvement.

Alteration of the airway microbiota is associated with the progression of post-COVID-19 chronic cough in adults: a prospective study

Peiying Huang, Zhaowei Yang, Chen Zhan, Xiaojun Xiao, Zexuan Lian, Liman Fang, Shuxin Zhong, Jiahan Xu, Mo Xian, Naijian Li, Xinru Wang, Jing Li, Ruchong Chen

2024, 51(10): 1111-1120. doi: 10.1016/j.jgg.2024.06.015

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Cough is one of the most common symptoms observed in patients presenting with COVID-19, persisting for an extended duration following SARS-CoV-2 infection. We aim to describe the distribution of airway microbiota and explore its role in patients with post-COVID-19 chronic cough. A total of 57 patients experiencing persistent cough after infection were recruited during the Omicron wave of SARS-CoV-2 in China. Airway microbiota profiling is assessed in nasopharyngeal swab, nasal lavage, and induced sputum samples at 4 and 8 weeks after SARS-CoV-2 infection. Our findings reveal that bacterial families Staphylococcaceae, Corynebacteriaceae, and Enterobacteriaceae are the most prevalent in the upper airway, while Streptococcaceae, Lachnospiraceae, and Prevotellaceae emerge as the most prevalent bacterial families in the lower airway. An increase in the abundance of Staphylococcus in nasopharyngeal swab samples and of Streptococcus in induced sputum samples is observed after one month. Furthermore, the abundance of Staphylococcus identified in nasopharyngeal swab samples at the baseline period emerges as an insightful predictor for improvement in cough severity. In conclusion, dynamic alterations in the airway microbial composition may contribute to the post-COVID-19 chronic cough progression, while the compositional signatures of nasopharyngeal microbiota could reflect the improvement of this disease.

Synergy of gut microbiota and host genome in driving heterosis expression of chickens

Qiang Huang, Chaoliang Wen, Shuang Gu, Yuchen Jie, Guangqi Li, Yiyuan Yan, Chuanyao Tian, Guiqin Wu, Ning Yang

2024, 51(10): 1121-1134. doi: 10.1016/j.jgg.2024.06.011

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Heterosis has been widely utilized in agricultural production. Despite over a century of extensive research, the underlying mechanisms of heterosis remain elusive. Most hypotheses and research have focused on the genetic basis of heterosis. However, the potential role of gut microbiota in heterosis has been largely ignored. Here, we carefully design a crossbreeding experiment with two distinct broiler breeds and conduct 16S rRNA amplicon and transcriptome sequencing to investigate the synergistic role of gut microbiota and host genes in driving heterosis. We find that the breast muscle weight of hybrids exhibits a high heterosis, 6.28% higher than the mid-parent value. A notable difference is observed in the composition and potential function of cecal microbiota between hybrids and their parents. Over 90% of differentially colonized microbiota and differentially expressed genes exhibit nonadditive patterns. Integrative analyses uncover associations between nonadditive genes and nonadditive microbiota, including a connection between the expression of cellular signaling pathways and metabolism-related genes and the abundance of Odoribacter, Oscillibacter, and Alistipes in hybrids. Moreover, higher abundances of these microbiota are related to better meat yield. In summary, these findings highlight the importance of gut microbiota in heterosis, serving as crucial factors that modulate heterosis expression in chickens.

H3K36me3 and H2A.Z coordinately modulate flowering time in Arabidopsis