Journal of Genetics and Genomics

Mechanism of cancer: Oncohistones in action

Lei Qiu, Xiaoyan Hu, Qian Jing, Xinyi Zeng, Kui-Ming Chan, Junhong Han

2018, 45(5): 227-236. doi: 10.1016/j.jgg.2018.04.004

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Abstract:
Oncohistones are histones with high-frequency point mutations that are associated with tumorigenesis. Although each histone variant is encoded by multiple genes, a single mutation in one allele of one gene seems to have a dominant effect over global histone H3 methylation level at the relevant amino acid residue. These oncohistones are highly tumor type specific. For example, H3K27M and H3G34V/R mutations occur only in pediatric brain cancers, whereas H3K36M and H3G34W/L have only been found in pediatric bone tumors. H1 mutations also seem to be exclusively linked to lymphomas. In this review, we discuss the occurrence, frequency and potential functional mechanisms of each oncohistone in tumorigenesis of its relevant cancer. We believe that further investigation into the mechanism regarding their tumor type specificity and cancer-related functions will shed new light on their application in cancer diagnosis and targeted therapy development.

Reduced Smoothened level rescues Aβ-induced memory deficits and neuronal inflammation in animal models of Alzheimer's disease

Weiwei Ma, Mengnan Wu, Siyan Zhou, Ye Tao, Zuolei Xie, Yi Zhong

2018, 45(5): 237-246. doi: 10.1016/j.jgg.2018.05.001

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Abstract:
Emerging evidence suggests that neuro-inflammation begins early and drives the pathogenesis of Alzheimer's disease (AD), and anti-inflammatory therapies are under clinical development. However, several anti-inflammatory compounds failed to improve memory in clinical trials, indicating that reducing inflammation alone might not be enough. On the other hand, neuro-inflammation is implicated in a number of mental disorders which share the same therapeutic targets. Based on these observations, we screened a batch of genes related with mental disorder and neuro-inflammation in a classical olfactory conditioning in an amyloid beta (Aβ) overexpression fly model. A Smoothened (SMO) mutant was identified as a genetic modifier of Aβ toxicity in 3-min memory and downregulation of SMO rescued Aβ-induced 3-min and 1-h memory deficiency. Also, Aβ activated innate inflammatory response in fly by increasing the expression of antimicrobial peptides, which were alleviated by downregulating SMO. Furthermore, pharmaceutical administration of a SMO antagonist LDE rescued Aβ-induced upregulation of SMO in astrocytes of mouse hippocampus, improved memory in Morris water maze (MWM), and reduced expression of astrocyte secreting pro-inflammatory factors IL-1β, TNFα and the microglia marker IBA-1 in anAPP/PS1 transgenic mouse model. Our study suggests that SMO is an important conserved modulator of Aβ toxicity in both fly and mouse models of AD.

Yeast KEOPS complex regulates telomere length independently of its t6A modification function

Ying-Ying Liu, Ming-Hong He, Jia-Cheng Liu, Yi-Si Lu, Jing Peng, Jin-Qiu Zhou

2018, 45(5): 247-257. doi: 10.1016/j.jgg.2018.03.004

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Abstract:
In Saccharomyces cerevisiae, the highly conserved Sua5 and KEOPS complex (including five subunits Kae1, Bud32, Cgi121, Pcc1 and Gon7) catalyze a universal tRNA modification, namely N⁶-threonylcarbamoyladenosine (t⁶A), and regulate telomere replication and recombination. However, whether telomere regulation function of Sua5 and KEOPS complex depends on the t⁶A modification activity remains unclear. Here we show that Sua5 and KEOPS regulate telomere length in the same genetic pathway. Interestingly, the telomere length regulation by KEOPS is independent of its t⁶A biosynthesis activity. Cytoplasmic overexpression of Qri7, a functional counterpart of KEOPS in mitochondria, restores cytosolic tRNA t⁶A modification and cell growth, but is not sufficient to rescue telomere length in the KEOPS mutant kae1Δ cells, indicating that a t⁶A modification-independent function is responsible for the telomere regulation. The results of our in vitro biochemical and in vivo genetic assays suggest that telomerase RNA TLC1 might not be modified by Sua5 and KEOPS. Moreover, deletion of KEOPS subunits results in a dramatic reduction of telomeric G-overhang, suggesting that KEOPS regulates telomere length by promoting G-overhang generation. These findings support a model in which KEOPS regulates telomere replication independently of its function on tRNA modification.

Whole-genome RNAi screen identifies methylation-related genes influencing lipid metabolism in Caenorhabditis elegans

Xiaotong Zhu, Yangli Liu, Hong Zhang, Pingsheng Liu

2018, 45(5): 259-272. doi: 10.1016/j.jgg.2018.03.005

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Abstract:
Lipid droplets (LDs) are highly conserved multifunctional cellular organelles and aberrant lipid storage in LDs can lead to many metabolic diseases. However, the molecular mechanisms governing lipid dynamic changes remain elusive, and the high-throughput screen of genes influencing LD morphology was limited by lacking specific LD marker proteins in the powerful genetic tool Caenorhabditis elegans. In this study, we established a new method to conduct whole-genome RNAi screen using LD resident protein DHS-3 as a LD marker, and identified 78 genes involved in significant LD morphologic changes. Among them, mthf-1, as well as a series of methylation-related genes, was found dramatically influencing lipid metabolism. SREBP-1 and SCD1 homologs in C. elegans were involved in the lipid metabolic change of mthf-1(RNAi) worms, and the regulation of ATGL-1 also contributed to it by decreasing triacylglycerol (TAG) hydrolysis. Overall, this study not only identified important genes involved in LD dynamics, but also provided a new tool for LD study usingC. elegans, with implications for the study of lipid metabolic diseases.

Germline silencing of UASt depends on the piRNA pathway

Yi-Chun Huang, Henry Moreno, Sarayu Row, Dongyu Jia, Wu-Min Deng

2018, 45(5): 273-276. doi: 10.1016/j.jgg.2018.04.005

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Abstract:

CRISPR/Cas9-edited Pax6-GFP reporter system facilitates the generation of mouse neural progenitor cells during differentiation

Yanni Li, Xu Li, Haisong Wang, Qian Gao, Jinxin Zhang, Wenhao Zhang, Zhisong Zhang, Luyuan Li, Yang Yu, Ling Shuai

2018, 45(5): 277-280. doi: 10.1016/j.jgg.2018.03.002

Abstract (84) HTML PDF (4)

Abstract:

2018 Vol. 45, No. 5