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"Fang, Jian"
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Genetic basis and biotechnological manipulation of sexual dimorphism and sex determination in fish
Aquaculture has made an enormous contribution to the world food production, especially to the sustainable supply of animal proteins. The utility of diverse reproduction strategies in fish, such as the exploiting use of unisexual gynogenesis, has created a typical case of fish genetic breeding. A number of fish species show substantial sexual dimorphism that is closely linked to multiple economic traits including growth rate and body size, and the efficient development of sex-linked genetic markers and sex control biotechnologies has provided significant approaches to increase the production and value for commercial purposes. Along with the rapid development of genomics and molecular genetic techniques, the genetic basis of sexual dimorphism has been gradually deciphered, and great progress has been made in the mechanisms of fish sex determination and identification of sex-determining genes. This review summarizes the progress to provide some directive and objective thinking for further re- search in this field.
Journal Article
5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs
Although 5-methylcytosine (m
5
C) is a widespread modification in RNAs, its regulation and biological role in pathological conditions (such as cancer) remain unknown. Here, we provide the single-nucleotide resolution landscape of messenger RNA m
5
C modifications in human urothelial carcinoma of the bladder (UCB). We identify numerous oncogene RNAs with hypermethylated m
5
C sites causally linked to their upregulation in UCBs and further demonstrate YBX1 as an m
5
C ‘reader’ recognizing m
5
C-modified mRNAs through the indole ring of W65 in its cold-shock domain. YBX1 maintains the stability of its target mRNA by recruiting ELAVL1. Moreover, NSUN2 and YBX1 are demonstrated to drive UCB pathogenesis by targeting the m
5
C methylation site in the
HDGF
3′ untranslated region. Clinically, a high coexpression of NUSN2, YBX1 and HDGF predicts the poorest survival. Our findings reveal an unprecedented mechanism of RNA m
5
C-regulated oncogene activation, providing a potential therapeutic strategy for UCB.
Chen et al. provide an m
5
C landscape in bladder cancer and show m
5
C enrichment at oncogene mRNAs that promotes tumour progression. They identify YBX1 as the m
5
C ‘reader’ that recruits ELAVL1 to stabilize mRNAs.
Journal Article
Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma
PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that
MYC
or
MYCN
amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of
CDK18
, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensitizing GSCs. ATR inhibitor VE822 combined with PARPi extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity. These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and PARP is an effective strategy for GBM, even for low-Myc GSCs that do not respond to PARPi alone, and potentially other PARPi-refractory tumors.
PARP inhibitors are mainly used to treat BRCA1/2 mutated cancers. Here, the authors show that MYC amplified glioblastomas are sensitive to PARP inhibition due to CDK18 repression, which impairs ATR regulated homologous recombination repair, and that ATR inhibition sensitises glioblastomas to PARP inhibition.
Journal Article
Slimy partners: the mucus barrier and gut microbiome in ulcerative colitis
Ulcerative colitis (UC) is a chronic recurrent intestinal inflammatory disease characterized by high incidence and young onset age. Recently, there have been some interesting findings in the pathogenesis of UC. The mucus barrier, which is composed of a mucin complex rich in O-glycosylation, not only provides nutrients and habitat for intestinal microbes but also orchestrates the taming of germs. In turn, the gut microbiota modulates the production and secretion of mucins and stratification of the mucus layers. Active bidirectional communication between the microbiota and its ‘slimy’ partner, the mucus barrier, seems to be a continually performed concerto, maintaining homeostasis of the gut ecological microenvironment. Any abnormalities may induce a disorder in the gut community, thereby causing inflammatory damage. Our review mainly focuses on the complicated communication between the mucus barrier and gut microbiome to explore a promising new avenue for UC therapy.
Gut microbiome: Slimy symbiosis
Gaining a better understanding of the bidirectional communication between the gut microbiome and the colon’s mucus layer, which covers and protects intestinal tissue, could aid in developing effective treatments for ulcerative colitis (UC). Increasing evidence links gut microbiome imbalance to UC, a form of inflammatory bowel disease. Xiaohong Zhang at Ningbo University in China and co-workers have reviewed gut microbiome–mucus layer interactions. They report that the mucus layer, comprised of a firm sterile inner layer, and a loose, densely colonized outer layer, nourishes and provides a home for ‘good’ microbes, while excluding pathogens. In turn, good microbes promote mucus layer production and stratification. Without adequate dietary fiber, gut microbes over-consume the mucus layer, exposing intestinal tissue and causing inflammation. This article provides clue for investigating treatments for inflammatory bowel diseases, including UC.
Journal Article
Interferon regulatory factor 1 (IRF1) and anti-pathogen innate immune responses
The eponymous member of the interferon regulatory factor (IRF) family, IRF1, was originally identified as a nuclear factor that binds and activates the promoters of type I interferon genes. However, subsequent studies using genetic knockouts or RNAi-mediated depletion of IRF1 provide a much broader view, linking IRF1 to a wide range of functions in protection against invading pathogens. Conserved throughout vertebrate evolution, IRF1 has been shown in recent years to mediate constitutive as well as inducible host defenses against a variety of viruses. Fine-tuning of these ancient IRF1-mediated host defenses, and countering strategies by pathogens to disarm IRF1, play crucial roles in pathogenesis and determining the outcome of infection.
Journal Article
Diverse and variable sex determination mechanisms in vertebrates
Sex is prevalent in nature and sex determination is one of the most fundamental biological processes, while the way of initiating female and male development exhibits remarkable diversity and variability across vertebrates. The knowledge on why and how sex determination mechanisms evolve unusual plasticity remains limited. Here, we summarize sex determination systems, master sex-determining genes and gene-regulatory networks among vertebrates. Recent research advancements on sex determination system transition are also introduced and discussed in some non-model animals with multiple sex determination mechanisms. This review will provide insights into the origin, transition and evolutionary adaption of different sex determination strategies in vertebrates, as well as clues for future perspectives in this field.
Journal Article
Distinct and Cooperative Roles of amh and dmrt1 in Self-Renewal and Differentiation of Male Germ Cells in Zebrafish
Spermatogenesis is a fundamental process in male reproductive biology and depends on precise balance between self-renewal and differentiation of male germ cells. However, the regulative factors for controlling the balance are poorly understood. In this study, we examined the roles of amh and dmrt1 in male germ cell development by generating their mutants with Crispr/Cas9 technology in zebrafish. Amh mutant zebrafish displayed a female-biased sex ratio, and both male and female amh mutants developed hypertrophic gonads due to uncontrolled proliferation and impaired differentiation of germ cells. A large number of proliferating spermatogonium-like cells were observed within testicular lobules of the amh-mutated testes, and they were demonstrated to be both Vasa- and PH3-positive. Moreover, the average number of Sycp3- and Vasa-positive cells in the amh mutants was significantly lower than in wild-type testes, suggesting a severely impaired differentiation of male germ cells. Conversely, all the dmrt1-mutated testes displayed severe testicular developmental defects and gradual loss of all Vasa-positive germ cells by inhibiting their self-renewal and inducing apoptosis. In addition, several germ cell and Sertoli cell marker genes were significantly downregulated, whereas a prominent increase of Insl3-positive Leydig cells was revealed by immunohistochemical analysis in the disorganized dmrt1-mutated testes. Our data suggest that amh might act as a guardian to control the balance between proliferation and differentiation of male germ cells, whereas dmrt1 might be required for the maintenance, self-renewal, and differentiation of male germ cells. Significantly, this study unravels novel functions of amh gene in fish.
Journal Article
High-sensitivity acoustic sensors from nanofibre webs
Considerable interest has been devoted to converting mechanical energy into electricity using polymer nanofibres. In particular, piezoelectric nanofibres produced by electrospinning have shown remarkable mechanical energy-to-electricity conversion ability. However, there is little data for the acoustic-to-electric conversion of electrospun nanofibres. Here we show that electrospun piezoelectric nanofibre webs have a strong acoustic-to-electric conversion ability. Using poly(vinylidene fluoride) as a model polymer and a sensor device that transfers sound directly to the nanofibre layer, we show that the sensor devices can detect low-frequency sound with a sensitivity as high as 266 mV Pa
−1
. They can precisely distinguish sound waves in low to middle frequency region. These features make them especially suitable for noise detection. Our nanofibre device has more than five times higher sensitivity than a commercial piezoelectric poly(vinylidene fluoride) film device. Electrospun piezoelectric nanofibres may be useful for developing high-performance acoustic sensors.
Polymer nanofibres can be used to detect mechanical motion. Here, the authors use electrospun piezoelectric nanofibre webs to detect acoustic waves at frequencies below 500 Hz with a good sensitivity at low pressure levels, and study the impact of the fibres morphology and crystalline phase.
Journal Article
Virus genomes and virus-host interactions in aquaculture animals
Over the last 30 years, aquaculture has become the fastest growing form of agriculture production in the world, but its devel- opment has been hampered by a diverse range of pathogenic viruses. During the last decade, a large number of viruses from aquatic animals have been identified, and more than 100 viral genomes have been sequenced and genetically characterized. These advances are leading to better understanding about antiviral mechanisms and the types of interaction occurring between aquatic viruses and their hosts. Here, based on our research experience of more than 20 years, we review the wealth of genetic and genomic information from studies on a diverse range of aquatic viruses, including iridoviruses, herpesviruses, reoviruses, and rhabdoviruses, and outline some major advances in our understanding of virus-host interactions in animals used in aqua- culture.
Journal Article