Genetics and Genomics

Genetic analysis and preimplantation genetic diagnosis of Chinese Marfan syndrome patients Publication date: Available online 24 May 2019 Source: Journal of Genetics and Genomics Author(s): Meng Qin, Xiaohui Zhu, Zhe Zhang, Xuemin Li, Zhiqiang Yan, Yuqian Wang, Shuo Guan, Yihua He, Wenxin Zhang, Liying Yan, Jie Qiao, Xu Zhi

mTOR/miR-145-regulated exosomal GOLM1 promotes hepatocellular carcinoma through augmented GSK-3β/MMPs Publication date: Available online 18 May 2019 Source: Journal of Genetics and Genomics Author(s): Xiaochen Gai, Bufu Tang, Fangming Liu, Yuting Wu, Fang Wang, Yanling Jing, Fuqiang Huang, Di Jin, Ling Wang, Hongbing Zhang Abstract Golgi membrane protein 1 (GOLM1/GP73) is a serum marker of hepatocellular carcinoma (HCC). We have previously shown that mTOR promoted tumorigenesis of HCC through stimulating GOLM1 expression. In this study, we demonstrated that the mammalian target of rapamycin (mTOR) was a negative regulator of microRNA-145 (miR-145) expression. miR-145 inhibited GOLM1 expression by targeting a coding sequence of GOLM1gene. GOLM1 and miR-145 were inversely correlated in human HCC tissues. GOLM1-enriched exosomes activated the glycogen synthase kinase-3β/matrix metalloproteinases (GSK-3β/MMPs) signaling axis of recipient cells and accelerated cell proliferation and migration. In contrast, miR-145 suppressed tumorigenesis and metastasis. We suggest that mTOR/miR-145/GOLM1 signaling pathway should be targeted for HCC treatment.

Rare inherited missense variants of POGZ associate with autism risk and disrupt neuronal development Publication date: Available online 18 May 2019 Source: Journal of Genetics and Genomics Author(s): Wenjing Zhao, Jieqiong Tan, Tengfei Zhu, Jianjun Ou, Ying Li, Lu Shen, Huidan Wu, Lin Han, Yanling Liu, Xiangbin Jia, Ting Bai, Honghui Li, Xiaoyan Ke, Jingping Zhao, Xiaobing Zou, Zhengmao Hu, Hui Guo, Kun Xia Abstract Excess de novo likely gene-disruptive and missense variants within dozens of genes have been identified in autism spectrum disorder (ASD) and other neurodevelopmental disorders. However, many rare inherited missense variants of these high-risk genes have not been thoroughly evaluated. Here, we analyzed the rare missense variant burden of POGZ in a large cohort of ASD patients from the Autism Clinical and Genetic Resources in China (ACGC) and further dissected the functional effect of disease-associated missense variants on neuronal development. Our results showed a significant burden of rare missense variants in ASD patients compared to the control population (P = 4.6×10-5, OR = 3.96), and missense variants in ASD patients showed more severe predicted functional outcomes than those in controls. Furthermore, by leveraging published large-scale sequencing data of neurodevelopmental disorders (NDDs) and sporadic case reports, we identified 8 de novo missense variants of POGZ in NDD patients. Functional analysis revealed that two inherited, but not de novo, missense variants influenced the cellular localization of POGZ and failed to rescue the defects in neurite and dendritic spine development caused by Pogz knockdown. Significantly, L1CAM, an autism candidate gene, is differentially expressed in POGZ knockout cell lines. Reduced expression of L1cam was able to partially rescue the neurite length defects. Our study showed the important roles of rare inherited missense variants of POGZ in ASD risk and neuronal development and identified the potential downstream targets of POGZ, which are important for further molecular mechanism studies.

Ciliopathy-associated proteins are involved in vesicle distribution in sensory cilia Publication date: Available online 15 May 2019 Source: Journal of Genetics and Genomics Author(s): Ming Li, Wanzhong He, Wei Li, Guangshuo Ou

HDAC6 regulates lipid droplet turnover in response to nutrient deprivation via p62-mediated selective autophagy Publication date: 20 April 2019 Source: Journal of Genetics and Genomics, Volume 46, Issue 4 Author(s): Yan Yan, Hao Wang, Chuanxian Wei, Yuanhang Xiang, Xuehong Liang, Chung-Weng Phang, Renjie Jiao Abstract Autophagy has been evolved as one of the adaptive cellular processes in response to stresses such as nutrient deprivation. Various cellular cargos such as damaged organelles and protein aggregates can be selectively degraded through autophagy. Recently, the lipid storage organelle, lipid droplet (LD), has been reported to be the cargo of starvation-induced autophagy. However, it remains largely unknown how the autophagy machinery recognizes the LDs and whether it can selectively degrade LDs. In this study, we show that Drosophila histone deacetylase 6 (dHDAC6), a key regulator of selective autophagy, is required for the LD turnover in the hepatocyte-like oenocytes in response to starvation. HDAC6 regulates LD turnover via p62/SQSTM1 (sequestosome 1)-mediated aggresome formation, suggesting that the selective autophagy machinery is required for LD recognition and degradation. Furthermore, our results show that the loss of dHDAC6 causes steatosis in response to starvation. Our findings suggest that there is a potential link between selective autophagy and susceptible predisposition to lipid metabolism associated diseases in stress conditions.

Understanding the importance of autophagy in human diseases using Drosophila Publication date: 20 April 2019 Source: Journal of Genetics and Genomics, Volume 46, Issue 4 Author(s): Arindam Bhattacharjee, Áron Szabó, Tamás Csizmadia, Hajnalka Laczkó-Dobos, Gábor Juhász Abstract Autophagy is a lysosome-dependent intracellular degradation pathway that has been implicated in the pathogenesis of various human diseases, either positively or negatively impacting disease outcomes depending on the specific context. The majority of medical conditions including cancer, neurodegenerative diseases, infections and immune system disorders and inflammatory bowel disease could probably benefit from therapeutic modulation of the autophagy machinery. Drosophila represents an excellent model animal to study disease mechanisms thanks to its sophisticated genetic toolkit, and the conservation of human disease genes and autophagic processes. Here, we provide an overview of the various autophagy pathways observed both in flies and human cells (macroautophagy, microautophagy and chaperone-mediated autophagy), and discuss Drosophila models of the above-mentioned diseases where fly research has already helped to understand how defects in autophagy genes and pathways contribute to the relevant pathomechanisms.

Understanding human diseases using Drosophila Publication date: 20 April 2019 Source: Journal of Genetics and Genomics, Volume 46, Issue 4 Author(s): Jun-Yuan Ji, Chun Han, Wu-Min Deng

Perspectives on gene expression regulation techniques in Drosophila Publication date: 20 April 2019 Source: Journal of Genetics and Genomics, Volume 46, Issue 4 Author(s): Rong-Gang Xu, Xia Wang, Da Shen, Jin Sun, Huan-Huan Qiao, Fang Wang, Lu-Ping Liu, Jian-Quan Ni Abstract Gene expression regulation, including loss-of-function and gain-of-function assays, is a powerful method to study developmental and disease mechanisms. Drosophila melanogaster is an ideal model system particularly well-equipped with many genetic tools. In this review, we describe and discuss the gene expression regulation techniques recently developed and their applications, including the CRISPR/Cas9-triggered heritable mutation system, CRISPR/dCas9-based transcriptional activation (CRISPRa) system, and CRISPR/dCas9-based transcriptional repression (CRISPRi) system, as well as the next-generation transgenic RNAi system. The main purpose of this review is to provide the fly research community with an updated summary of newly developed gene expression regulation techniques and help the community to select appropriate methods and optimize the research strategy.

Lipid storage regulator CdsA is essential for Drosophila metamorphosis Publication date: 20 April 2019 Source: Journal of Genetics and Genomics, Volume 46, Issue 4 Author(s): Yuan Liu, Yuan Ji, Xia Li, Guanghou Shui, Xun Huang

Human mitochondrial DNA diseases and Drosophila models Publication date: 20 April 2019 Source: Journal of Genetics and Genomics, Volume 46, Issue 4 Author(s): Zhe Chen, Fan Zhang, Hong Xu Abstract Mutations that disrupt the mitochondrial genome cause a number of human diseases whose phenotypic presentation varies widely among tissues and individuals. This variability owes in part to the unconventional genetics of mitochondrial DNA (mtDNA), which includes polyploidy, maternal inheritance and dependence on nuclear-encoded factors. The recent development of genetic tools for manipulating mitochondrial genome in Drosophila melanogaster renders this powerful model organism an attractive alternative to mammalian systems for understanding mtDNA-related diseases. In this review, we summarize mtDNA genetics and human mtDNA-related diseases. We highlight existing Drosophila models of mtDNA mutations and discuss their potential use in advancing our knowledge of mitochondrial biology and in modeling human mitochondrial disorders. We also discuss the potential and present challenges of gene therapy for the future treatment of mtDNA diseases.

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