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circadian control of hematopoiesis through the histone methylransferase Ezh2 in zebrafish

Circadian control of hematopoiesis through the histone methy...

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2015年中国中西医结合学会时间生物医学专业委员会学术...

作者： ZHONG Yingbin YE Qiang HUANG Guodong WANG Mingyong WANG Han Center for circadian clocks Soochow University School of Biology & Basic Medical Sciences Medical CollegeSoochow University

circadian rhythms are endogenous oscillations generated by an interlocking positive and negative transcriptional/translational feedback *** in chromatin structure derived from post-translational modifications of histone are required for transcriptional regulation of genes including circadian clock ***2,a polycomb group enzyme that methylates lysine 27 on histone H3,was shown to be essential for mouse liver circadian *** deletion of mouse Ezh2 results in embryonic lethality,whether EZH2 contributes to circadian regulation of other organs remains to be *** we showed that zebrafishezh2 is rhythmically expressed in wild-type larvae under both DD and LD conditions,is up-regulated in the per1 b mutant and show antiphasic expression in the per2 *** assays showed that Bmal1 b binds to the E-box and E’-box and Per2 binds to the RRE on the ezh2 promoter,implicating that the circadian clock directly controls ***,circadian clock genes such as per1 a,per1b,per3,per3,cry1 aa,cry1ab,cry1 baand cry1bbare all down-regulated in homozygous ezh2 mutant zebrafish;zebrafish treated with GSK126(an EZH2 inhibitor) display lengthened period,increased amplitude and phase-delay;and Ezh2 binds to Bmal1b-Clock1 a and enhances the transcription activity of Bmal1b-Clock1a;whereby indicating thatzebrafish Ezh2 contributes to circadian *** ezh2 mutant fish displays defects in circulation and die around 5 dpf,and reduced circulation in this mutant is due to altered primitive and definitive hematopoiesis,as shown byin situ hybridization and ***,rhythmic expression of some hematopoietic markers are disrupted in ezh2 and clock gene zebrafish ***,these results demonstrate thatEzh2 plays important roles in circadian regulation and the circadian clock acts through Ezh2 to contribute to hematopoiesis in zebrafish.

关键词： Ezh2 hematopoesis epigenetic regualtion circadian clocks zebrafish

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A circadian model for attention deficit and hyperactivity disorder(ADHD)

A circadian model for attention deficit and hyperactivity di...

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中国遗传学会第九次全国会员代表大会暨学术研讨会

作者：王晗 Center for circadian clocks Soochow University

Attention Deficit/Hyperactivity Disorder(ADHD) is one of the most prevalent psychiatric disorders in children and adults,affecting approximately 3-5%of the population ADHD is characterized clinically by hyperactivity,impulsivity and *** we report an insertional mutant wherein the retroviral insertion abolishes the transcription of zebrafish periodlb (perlb).PER1B inhibits zebrafish perla,per2,and per3 but upregulates ADHD-susceptibility gene lphn3.1.A group of behavioral assays demonstrated that homozygous perlb(-/-) larvae and adult fish are hyperactive,impulsive and inattentive,reminiscent of human ADHD *** of perlb function results in upregulation of the two genes(dbh,and mao) involved in dopamine degradation but downregulation of transcription factors(otpa and otpb) and signaling proteins (wntl and wnt5al) involved in differentiation and development of the dopaminergic(DA) neurons in homozygous perlb(-/-).The latter could be responsible for partial loss of dopaminergic neurons in the posterior tuberculum(PT) of the ventral diencephalon in homozygous perlb(-/-).Therefore, the homozygous perlb(-/-) larvae and adult fish produce significantly reduced amount of endogenous ***,the mutant behavioral abnormality can be rescued by wild type perlb and the ADHD treatment drug *** studies for the first time demonstrated that disruption of a circadian clock gene elicits ADHD-like syndromes,and these unique ADHD animal models should open avenues for exploring novel targets for ADHD diagnosis and treatment.

关键词： ADHD Dopaminergic neuron circadian clocks Zebrafish

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circadian clock protein Period3 contributes to sleep homeostasis through histamine and GABA signaling in zebrafish

Circadian clock protein Period3 contributes to sleep homeost...

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中国神经科学学会第十二届全国学术会议

作者： Zhaomin ZHONG Xiaona XU Han WANG Center for circadian clocks Soochow University

The zebrafish（Danio rerio） has figured prominently as a vertebrate model for studying circadian clocks and sleep. It is known that both the homeostatic process（S） and the circadian process（C） contribute to regulation of sleep homeostasis. While we have a good understanding of circadian regulation, relatively little is known about molecular mechanisms underlying circadian regulation of sleep homeostasis and/or interaction between the circadian clock system and sleep. Here we reported characterization of zebrafish period3（per3） null mutants generated by TALEN. Locomotor assays showed that per3 mutant fish display 0.5-hour shortened period and approximately 3-hour phase advance compared with wild types under constant dark, and are completely arrhythmic under constant light;and also per1 a, per1 b and per2 are down-regulated in per3 mutant fish;indicating that per3 is essential for zebrafish circadian regulation. Intriguingly, per3 mutant fish display less sleep time, elevated arousal threshold and difficulty to restore sleep after sleep deprivation. As shown by ELISA, the GABA level is reduced while the histamine level is increased in per3 mutant fish at night-time, indicating that the disturbed sleep pattern of per3 mutant fish may be resulted from altered levels of endogenous GABA and histamine. Deep sequencing-based transcriptome analysis leads us to focus on two candidate genes, GABA A receptor gene rho2 a and histamine decarboxylase gene hdc, both up-regulated in the per3 mutant fish. Luciferase reporter assays showed that both rho2 a and hdc are circadian clock-controlled genes and Per3 negatively regulates their expression. Taken together, these results ascertain Per3’s essential roles in the zebrafish circadian system, demonstrate that Per3 acts through both histamine signaling and GABA signaling to contribute to sleep regulation, and provide an ideal sleep disorder vertebrate model for drug screen and pathogenesis analysis.

关键词： circadian clocks Per3 Sleep GABA Histamine

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Ezh2 promotes clock function and hematopoiesis independent of histone methyltransferase activity in zebrafish

Ezh2 promotes clock function and hematopoiesis independent o...

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2018中国遗传学会第十次全国会员代表大会暨学术讨论会

作者： Yingbin Zhong Chengyan Chen Han Wang Center for circadian clocks Soochow University School of Biology ＆ Basic Medical Sciences Medical College Soochow University

EZH2 is a subunit of polycomb repressive complex 2（PRC2） that silences gene transcription via H3 K27 me3 and was shown to be essential for mammalian liver circadian regulation and hematopoiesis through gene silencing. Much less, however, is known about how Ezh2 acts in live zebrafish. Here, we show that zebrafish ezh2 is regulated directly by the circadian clock via both E-box and RORE motif, while core circadian clock genes per1 a, per1 b, cry1 aa and cry1 ab are down-regulated in ezh2 null mutant and ezh2 morphant zebrafish, and either knockdown or overexpression of ezh2 alters locomotor rhythms, indicating that Ezh2 is required for zebrafish circadian regulation. In contrast to its canonical silencing function, zebrafish Ezh2 up-regulates these key circadian clock genes independent of histone methyltransferase activity by directly binding to key circadian clock proteins. Similarly, Ezh2 contributes to hematopoiesis by enhancing expression of hematopoietic genes such as cmyb and lck. Together, our findings demonstrate for the first time that Ezh2 acts in both circadian regulation and hematopoiesis independent of silencing PRC2.

关键词： circadian clocks PRC2 ezh2 hematopoiesis zebrafish

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