Journal of Genetics and Genomics

Peripheral and central control of obesity by primary cilia

Yue Wu, Jun Zhou, Yunfan Yang

2023, 50(5): 295-304. doi: 10.1016/j.jgg.2022.12.006

Abstract (149) PDF (17)

Abstract:
Primary cilia are hair-like structures that protrude from the cell surface. They are capable of sensing external cues and conveying a vast array of signals into cells to regulate a variety of physiological activities. Mutations in cilium-associated genes are linked to a group of diseases with overlapping clinical manifestations, collectively known as ciliopathies. A significant proportion of human ciliopathy cases are accompanied by metabolic disorders such as obesity and type 2 diabetes. Nevertheless, the mechanisms through which dysfunction of primary cilia contributes to obesity are complex. In this review, we present an overview of primary cilia and highlight obesity-related ciliopathies. We also discuss the potential role of primary cilia in peripheral organs, with a focus on adipose tissues. In addition, we emphasize the significance of primary cilia in the central regulation of obesity, especially the involvement of ciliary signaling in the hypothalamic control of feeding behavior. This review therefore proposes a framework of both peripheral and central regulation of obesity by primary cilia, which may benefit further exploration of the ciliary role in metabolic regulation.

Decoding transcriptional regulation via a human gene expression predictor

Yuzhou Wang, Yu Zhang, Ning Yu, Bingyan Li, Jiazhen Gong, Yide Mei, Jianqiang Bao, Shisong Ma

2023, 50(5): 305-317. doi: 10.1016/j.jgg.2023.01.006

Abstract (188) PDF (18)

Abstract:
Transcription factors (TFs) regulate cellular activities by controlling gene expression, but a predictive model describing how TFs quantitatively modulate human transcriptomes is lacking. We construct a universal human gene expression predictor named EXPLICIT-Human and utilize it to decode transcriptional regulation. Using the expression of 1613 TFs, the predictor reconstitutes highly accurate transcriptomes for samples derived from a wide range of tissues and conditions. The broad applicability of the predictor indicates that it recapitulates the quantitative relationships between TFs and target genes ubiquitous across tissues. Significant interacting TF-target gene pairs are extracted from the predictor and enable downstream inference of TF regulators for diverse pathways involved in development, immunity, metabolism, and stress response. A detailed analysis of the hematopoiesis process reveals an atlas of key TFs regulating the development of different hematopoietic cell lineages, and a portion of these TFs are conserved between humans and mice. The results demonstrate that our method is capable of delineating the TFs responsible for fate determination. Compared to other existing tools, EXPLICIT-Human shows a better performance in recovering the correct TF regulators.

Phosphatidylcholine deficiency increases ferroptosis susceptibility in the Caenorhabditis elegans germline

Jinglin Zhu, Wei Meng, Sin Man Lam, Guanghou Shui, Xun Huang

2023, 50(5): 318-329. doi: 10.1016/j.jgg.2023.03.005

Abstract (279) PDF (24)

Abstract:
Ferroptosis, a regulated and iron-dependent form of cell death characterized by peroxidation of membrane phospholipids, has tremendous potential for the therapy of human diseases. The causal link between phospholipid homeostasis and ferroptosis is incompletely understood. Here, we reveal that spin-4, a previously identified regulator of the “B12-one-carbon cycle-phosphatidylcholine (PC)” pathway, sustains germline development and fertility by ensuring PC sufficiency in the nematode Caenorhabditis elegans. Mechanistically, SPIN-4 regulates lysosomal activity which is required for B12-associated PC synthesis. PC deficiency-induced sterility can be rescued by reducing the levels of polyunsaturated fatty acids, reactive oxygen species, and redox-active iron, which indicates that the sterility is mediated by germline ferroptosis. These results highlight the critical role of PC homeostasis in ferroptosis susceptibility and offer a new target for pharmacological approaches.

Lack of evolutionary convergence in multiple primary lung cancer suggests insufficient specificity of personalized therapy

Hua Cheng, Ziyan Guo, Xiaoyu Zhang, Xiao-Jin Wang, Zizhang Li, Wen-Wen Huo, Hong-Cheng Zhong, Xiao-Jian Li, Xiang-Wen Wu, Wen-Hao Li, Zhuo-Wen Chen, Tian-Chi Wu, Xiang-Feng Gan, Bei-Long Zhong, Vassily A. Lyubetsky, Leonid Yu Rusin, Junnan Yang, Qiyi Zhao, Qing-Dong Cao, Jian-Rong Yang

2023, 50(5): 330-340. doi: 10.1016/j.jgg.2022.11.005

Abstract (186) PDF (12)

Abstract:
Multiple primary lung cancer (MPLC) is an increasingly prevalent subtype of lung cancer. According to recent genomic studies, the different lesions of a single MPLC patient exhibit functional similarities that may reflect evolutionary convergence. We perform whole-exome sequencing for a unique cohort of MPLC patients with multiple samples from each lesion found. Using our own and other relevant public data, evolutionary tree reconstruction reveals that cancer driver gene mutations occurred at the early trunk, indicating evolutionary contingency rather than adaptive convergence. Additionally, tumors from the same MPLC patient are as genetically diverse as those from different patients, while within-tumor genetic heterogeneity is significantly lower. Furthermore, the aberrant molecular functions enriched in mutated genes for a sample show a strong overlap with other samples from the same tumor, but not with samples from other tumors or other patients. Overall, there is no evidence of adaptive convergence during the evolution of MPLC. Most importantly, the similar between-tumor diversity and between-patient diversity suggest that personalized therapies may not adequately account for the genetic diversity among different tumors in an MPLC patient. To fully exploit the strategic value of precision medicine, targeted therapies should be designed and delivered on a per-lesion basis.

Diverse interactions of five core type III effectors from Ralstonia solanacearum with plants

Shen Cong, Jun-Zhou Li, Zheng-Zhong Xiong, Hai-Lei Wei

2023, 50(5): 341-352. doi: 10.1016/j.jgg.2022.04.018

Abstract (394) PDF (36)

Abstract:
Ralstonia solanacearum is a widespread plant bacterial pathogen that can launch a range of type III effectors (T3Es) to cause disease. In this study, we isolate a pathogenic R. solanacearum strain named P380 from tomato rhizosphere. Five out of 12 core T3Es of strain P380 are introduced into Pseudomonas syringae DC3000D36E separately to determine their functions in interacting with plants. DC3000D36E that harbors each effector suppresses FliC-triggered Pti5 and ACRE31 expression, ROS burst, and callose deposition. RipAE, RipU, and RipW elicit cell death as well as upregulate the MAPK cascades in Nicotiana benthamiana. The derivatives RipC1^ΔDXDX(T/V) and RipW^ΔDKXXQ but not RipAE^K310R fail to suppress ROS burst. Moreover, RipAE^K310R and RipW^ΔDKXXQ retain the cell death elicitation ability. RipAE and RipW are associated with salicylic acid and jasmonic acid pathways, respectively. RipAE and RipAQ significantly promote the propagation of DC3000D36E in plants. The five core T3Es localize in diverse subcellular organelles of nucleus, plasma membrane, endoplasmic reticulum, and Golgi network. The suppressor of G2 allele of Skp1 is required for RipAE but not RipU-triggered cell death in N. benthamiana. These results indicate that the core T3Es in R. solanacearum play diverse roles in plant-pathogen interactions.

A strategy for uncovering germline variants altering anti-tumor CD8 T cell response

Vijay Kumar Ulaganathan, Martina H. Vasileva

2023, 50(5): 353-361. doi: 10.1016/j.jgg.2023.01.001

Abstract (144) PDF (10)

Abstract:
Among many factors known to alter the outcomes of T cell receptor (TCR)-induced proximal signaling, the role of human germline variants in dictating the individuality of the anti-tumor CD8 T cell response has remained challenging to address. Here, we describe a convenient strategy for molecular and functional characterization of phosphotyrosine-altering non-synonymous single nucleotide variations (pTyr-SNVs) that directly impact TCR-induced proximal phosphotyrosine motif-based signaling pathways. We devise an experimental co-cultivation set-up comprising a C57BL/6 mouse-derived metastatic melanoma cell line engineered to constitutively present ovalbumin (OVA) antigens and retrovirally engineered syngeneic major histocompatibility complex (MHC) Class I restricted OVA TCR-transgenic CD8 T cells (OT-I). Using the synthetic version of pTyr-SNV rs1178800678-G/T-encoding integrin alpha 4 (ITGA4) p.S1027I variant as a prototype, we show that under identical TCR stimulation conditions, genetically determined membrane-proximal immunoreceptor tyrosin activation motif (ITAM) results in increased tyrosine phosphorylation of 70 kDa zeta-chain-associated protein (ZAP70) and the levels of cytotoxic effector molecule granzyme B (GZMB), which in turn result in enhanced cytotoxic activity against metastatic melanoma cell line. This strategy paves the way for rapid molecular and functional characterization of anti-tumor immune response-linked germline pTyr-SNVs so as to improve our understanding of the genetic basis of individual-to-individual differences in anti-tumor CD8 T cell response.

Whole-genome sequencing reveals selection signals among Chinese, Pakistani, and Nepalese goats

Yefang Li, Ying Gong, Zhengkai Zhang, Ling Li, Xuexue Liu, Xiaohong He, Qianjun Zhao, Yabin Pu, Yuehui Ma, Lin Jiang

2023, 50(5): 362-365. doi: 10.1016/j.jgg.2023.01.010

Abstract (338) PDF (83)

Abstract:

Development of a haploid inducer by editing HvMTL in barley

Huali Tang, Yuliang Qiu, Wanxin Wang, Mei Yu, Yanan Chang, Zhiyang Han, Lipu Du, Zhishan Lin, Ke Wang, Xingguo Ye

2023, 50(5): 366-369. doi: 10.1016/j.jgg.2022.11.007

Abstract (343) PDF (60)

Abstract:

SUN3/4/5 proteins regulate endoplasmic reticulum tubule formation and luminal spacing in Arabidopsis

Yong Xue, Peng-Fei Jia, Hong-Ju Li

2023, 50(5): 370-373. doi: 10.1016/j.jgg.2022.11.004

Abstract (311) PDF (45)

Abstract:

2023 Vol. 50, No. 5