Journal of Genetics and Genomics

Understanding the mechanistic regulation of ferroptosis in cancer: the gene matters

Min Gao, Kexin Fan, Yuhan Chen, Guangjian Zhang, Jing Chen, Yilei Zhang

2022, 49(10): 913-926. doi: 10.1016/j.jgg.2022.06.002

Abstract (407) PDF (29)

Abstract:
Ferroptosis has emerged as a crucial regulated cell death involved in a variety of physiological processes or pathological diseases, such as tumor suppression. Though initially being found from anticancer drug screening and considered not essential as apoptosis for growth and development, numerous studies have demonstrated that ferroptosis is tightly regulated by key genetic pathways and/or genes, including several tumor suppressors and oncogenes. In this review, we introduce the basic concepts of ferroptosis, characterized by the features of non-apoptotic, iron-dependent, and overwhelmed accumulation of lipid peroxides, and the underlying regulated circuits are considered to be pro-ferroptotic pathways. Then, we discuss several established lipid peroxidation defending systems within cells, including SLC7A11/GPX4, FSP1/CoQ, GCH1/BH4, and mitochondria DHODH/CoQ, all of which serve as anti-ferroptotic pathways to prevent ferroptosis. Moreover, we provide a comprehensive summary of the genetic regulation of ferroptosis via targeting the above-mentioned pro-ferroptotic or anti-ferroptotic pathways. The regulation of pro- and anti-ferroptotic pathways gives rise to more specific responses to the tumor cells in a context-dependent manner, highlighting the unceasing study and deeper understanding of mechanistic regulation of ferroptosis for the purpose of applying ferroptosis induction in cancer therapy.

Efficient multinucleotide deletions using deaminase-Cas9 fusions in human cells

Siyu Chen, Zhiquan Liu, Hao Yu, Liangxue Lai, Zhanjun Li

2022, 49(10): 927-933. doi: 10.1016/j.jgg.2022.03.007

Abstract (298) PDF (16)

Abstract:
CRISPR/Cas9 system is a robust genome editing platform in biotechnology and medicine. However, it generally produces small insertions/deletions (indels, typically 1–3 bp) but rarely induces larger deletions in specific target sites. Here, we report a cytidine deaminase-Cas9 fusion-induced deletion system (C-DEL) and an adenine deaminase-Cas9 fusion-induced deletion system (A-DEL) by combining Cas9 with rat APOBEC1 (rA1) and TadA 8e, respectively. Both C-DEL and A-DEL improve the efficiency of deletions compared with the conventional Cas9 system in human cells. In addition, the C-DEL system generates a considerable fraction of predictable multinucleotide deletions from 5′-deaminated C bases to the Cas9-cleavage site and increases the proportion of larger deletions at the target loci. Taken together, the C-DEL and A-DEL systems provide a practical strategy for producing efficient multinucleotide deletions, expanding the CRISPR/Cas9 toolsets for gene modifications in human cells.

Genetic evidence for facial variation being a composite phenotype of cranial variation and facial soft tissue thickness

Wei Qian, Manfei Zhang, Kaiwen Wan, Yunxia Xie, Siyuan Du, Jiarui Li, Xiongzheng Mu, Jiange Qiu, Xiangyang Xue, Xiahai Zhuang, Yingzhi Wu, Fan Liu, Sijia Wang

2022, 49(10): 934-942. doi: 10.1016/j.jgg.2022.02.020

Abstract (188) PDF (23)

Abstract:
Facial and cranial variation represent a multidimensional set of highly correlated and heritable phenotypes. Little is known about the genetic basis explaining this correlation. We develop a software package ALoSFL for simultaneous localization of facial and cranial landmarks from head computed tomography (CT) images, apply it in the analysis of head CT images of 777 Han Chinese women, and obtain a set of phenotypes representing variation in face, skull and facial soft tissue thickness (FSTT). Association analysis of 301 single nucleotide polymorphisms (SNPs) from 191 distinct genomic loci previously associated with facial variation reveals an unexpected larger number of loci showing significant associations (P < 1e–3) with cranial phenotypes than expected under the null (O/E = 3.39), suggesting facial and cranial phenotypes share a substantial proportion of genetic components. Adding FSTT to a SNP-only model shows a large impact in explaining facial variance. A gene ontology analysis reveals that bone morphogenesis and osteoblast differentiation likely underlie our cranial-significant findings. Overall, this study simultaneously investigates the genetic effects on both facial and cranial variation of the same sample, supporting that facial variation is a composite phenotype of cranial variation and FSTT.

The shikimate pathway regulates programmed cell death

Xuerui Lu, Shixi Shi, Chong Wu, Xueao Zheng, Chenkun Yang, Jie Luo, Shunping Yan

2022, 49(10): 943-951. doi: 10.1016/j.jgg.2022.02.001

Abstract (300) PDF (41)

Abstract:
Programmed cell death (PCD) is essential for both plant development and stress responses including immunity. However, how plants control PCD is not well-understood. The shikimate pathway is one of the most important metabolic pathways in plants, but its relationship to PCD is unknown. Here, we show that the shikimate pathway promotes PCD in Arabidopsis. We identify a photoperiod-dependent lesion-mimic mutant named Lesion in short-day (lis), which forms spontaneous lesions in short-day conditions. Map-based cloning and whole-genome resequencing reveal that LIS encodes MEE32, a bifunctional enzyme in the shikimate pathway. Metabolic analysis shows that the level of shikimate is dramatically increased in lis. Through genetic screenings, three suppressors of lis (slis) are identified and the causal genes are cloned. SLISes encode proteins upstream of MEE32 in the shikimate pathway. Furthermore, exogenous shikimate treatment causes PCD. Our study uncovers a link between the shikimate pathway and PCD, and suggests that the accumulation of shikimate is an alternative explanation for the action of glyphosate, the most successful herbicide.

The SNAPc complex mediates starvation-induced trans-splicing in Caenorhabditis elegans

Xinhao Hou, Chengming Zhu, Mingjing Xu, Xiangyang Chen, Cheng Sun, Björn Nashan, Shouhong Guang, Xuezhu Feng

2022, 49(10): 952-964. doi: 10.1016/j.jgg.2022.02.024

Abstract (158) PDF (8)

Abstract:
Dietary restriction usually suppresses biosynthesis but activates catabolic pathways in animals. However, the short-term starvation enhances biosynthetic activities and promotes ribosomal biogenesis in adult Caenorhabditis elegans. The mechanism underlying the processes remains largely unknown. Here, we find that the short-term starvation enhances the SL1 trans-splicing of translation-related genes in adult C. elegans by transcriptome analysis. The small nuclear RNA-activating protein complex (SNAPc) promotes SL RNA production and mediates starvation-induced trans-splicing. TOFU-5, a core factor in the upstream sequence transcription complex (USTC) essential for piRNA production, is also involved in the starvation-induced trans-splicing processes. Knocking down components of the SNAPc complex and tofu-5 extends worm survival under starvation conditions. Taken together, our study highlights the importance of SL trans-splicing in the nutrition response and reveals a mechanism of the survival regulation by food deprivation via SNAPc and TOFU-5.

Sources of transcription variation in Plasmodium falciparum

Lindsey B. Turnbull, Katrina A. Button-Simons, Nestor Agbayani, Michael T. Ferdig

2022, 49(10): 965-974. doi: 10.1016/j.jgg.2022.03.008

Abstract (234) PDF (9)

Abstract:
Variation in transcript abundance can contribute to both short-term environmental response and long-term evolutionary adaptation. Most studies are designed to assess differences in mean transcription levels and do not consider other potentially important and confounding sources of transcriptional variation. Detailed quantification of variation sources will improve our ability to detect and identify the mechanisms that contribute to genome-wide transcription changes that underpin adaptive responses. To quantify innate levels of expression variation, we measured mRNA levels for more than 5000 genes in the malaria parasite, Plasmodium falciparum, among clones derived from two parasite strains across biologically and experimentally replicated batches. Using a mixed effects model, we partitioned the total variation among four sources—between strain, within strain, environmental batch effects, and stochastic noise. We found 646 genes with significant variation attributable to at least one of these sources. These genes were categorized by their predominant variation source and further examined using gene ontology enrichment analysis to associate function with each source of variation. Genes with environmental batch effect and within strain transcript variation may contribute to phenotypic plasticity, while genes with between strain variation may contribute to adaptive responses and processes that lead to parasite strain-specific survival under varied conditions.

Long-read sequencing and de novo assembly of the cynomolgus macaque genome

Bing Bai, Yi Wang, Ran Zhu, Yaolei Zhang, Hong Wang, Guangyi Fan, Xin Liu, Hong Shi, Yuyu Niu, Weizhi Ji

2022, 49(10): 975-978. doi: 10.1016/j.jgg.2021.12.013

Abstract (294) PDF (70)

Abstract:

An efficient screening system to identify protein–protein or protein–DNA interaction partners of rice transcription factors

Qingmei Su, Fang Zhang, Yunping Xiao, Pingping Zhang, Hefei Xing, Fan Chen

2022, 49(10): 979-981. doi: 10.1016/j.jgg.2022.02.007

Abstract (496) PDF (81)

Abstract:

Efficient silencing of the multicopy DUX4 gene by ABE-mediated start codon mutation in human embryos

Yubing Liu, Xinmei Lu, Min Ye, Ling Wang, Rongxin Tang, Zhiyong Yang, Bongkoch Turathum, Chenchen Liu, Yujing Xue, Menghua Wu, Yannan Yang, Ermeng Gao, Di Zhang, Feng Yang, Keh-Kooi Kee, Xingxu Huang, Guanglei Li, Ri-Cheng Chian

2022, 49(10): 982-985. doi: 10.1016/j.jgg.2022.02.010

Abstract (715) PDF (31)

Abstract:

Arabidopsis CAP1 mediates ammonium-regulated root hair growth by influencing vesicle trafficking and the cytoskeletal arrangement in root hair cells

Juanjuan Yu, Xiaonan Ma, Lianlian Wang, Nannan Dong, Kai Wang, Qingye You, Yifei Xu, Chong Wang, Zhiping Dong, Zhaobin Shi, Shaojun Dai, Ling Bai, Chun-Peng Song

2022, 49(10): 986-989. doi: 10.1016/j.jgg.2022.02.005

Abstract (359) PDF (48)

Abstract:

2022 Vol. 49, No. 10