The circadian rhythm,a 24-h cycle,plays a crucial role in regulating gut physiological processes,particularly the proliferation and differentiation of intestinal epithelial cells,which are essential for gut homeostasi...The circadian rhythm,a 24-h cycle,plays a crucial role in regulating gut physiological processes,particularly the proliferation and differentiation of intestinal epithelial cells,which are essential for gut homeostasis and repair.This review discusses the complex interactions between circadian rhythms,cell cycle regulation,and key signaling pathways(Wnt,Notch,and Hippo)in the context of the intestinal stem cell niche and epithelial cell fate decisions.Key molecules such as brain and muscle ARNT-like 1(BMAL1),circadian locomotor output cycles kaput(CLOCK),hairy and enhancer of split 1(Hes1),and Yes-associated protein/transcriptional coactivator with PDZ-binding motif(YAP/TAZ)coordinate stem cell functions with circadian rhythms.We discuss how Notch signaling regulates the cell cycle and interacts with circadian rhythms.Additionally,we explore the role of Hippo-Wnt signaling in balancing cell proliferation and differentiation.Furthermore,we highlight the intricate relationships between circadian clock components and signaling pathways,emphasizing the importance of temporal coordination in determining epithelial cell fate.We also discuss shared enzymes,including casein kinase 1 delta(CK1δ),glycogen synthase kinase 3(GSK3),and AMP-activated protein kinase(AMPK),which play a role in regulating the cell cycle,circadian rhythm,and signaling pathways.In summary,this review offers valuable insights into the regulatory mechanisms that control stem cell behavior and epithelial cell differentiation,suggesting promising directions for future research in intestinal biology and tissue homeostasis.展开更多
The announcement of the Nobel Prize in Physiology or Medicine 2017 gave us a mixture of excitement and surprise.Although researchers in circadian rhythm community have been expecting this from the committee of Nobel P...The announcement of the Nobel Prize in Physiology or Medicine 2017 gave us a mixture of excitement and surprise.Although researchers in circadian rhythm community have been expecting this from the committee of Nobel Prize for quite a few years, several people had guessed that the Nobel Prize in Medicine this year would go to some scientists who discovered immune checkpoints or to those who developed gene editing tools. The Nobel Prize laureate is generally considered as a positive hero in modern science.展开更多
Purpose:Individual chronotypes are reported to be closely associated with mood,health status,and even disease progression.However,no reports of chronotype distribution in the Chinese population have been made availabl...Purpose:Individual chronotypes are reported to be closely associated with mood,health status,and even disease progression.However,no reports of chronotype distribution in the Chinese population have been made available to date.Methods:We performed a chronotype survey using the classic Morningness–Eveningness Questionnaire both online and offline.The webpage-based online survey was distributed via a social network application on mobile phones.The offline survey was distributed to local primary and middle schools.A total of 9476 questionnaires were collected,of which 8395 were valid.The mean age of the participants was 30.38±11.47 years,and 37.38%were male.Results:Overall,the Chinese chronotypes showed a near-normal distribution with a slight shift toward eveningness.When analyzed in different age groups,the overall Chinese population was shown to be"latest"in their early twenties.In the young population,two significant points of change in chronotype were identified at the ages of 10 and 16 years.The chronotype composition remained relatively stable during early adulthood(from 17 to 28 years of age).Conclusion:This study generated the first overview of chronotype distribution in the Chinese population and will serve as essential background data for future studies.展开更多
Chromatin modification contributes to pluripotency maintenance in embryonic stem cells(ESCs).However,the related mechanisms remain obscure.Here,we show that Npac,a"reader"of histone H3 lysine 36 trimethylati...Chromatin modification contributes to pluripotency maintenance in embryonic stem cells(ESCs).However,the related mechanisms remain obscure.Here,we show that Npac,a"reader"of histone H3 lysine 36 trimethylation(H3K36me3),is required to maintain mouse ESC(mESC)pluripotency since knockdown of Npac causes mESC differentiation.Depletion of Npac in mouse embryonic fibroblasts(MEFs)inhibits reprogramming efficiency.Furthermore,our chromatin immunoprecipitation followed by sequencing(ChIP-seq)results of Npac reveal that Npac co-localizes with histone H3K36me3 in gene bodies of actively transcribed genes in mESCs.Interestingly,we find that Npac interacts with positive transcription elongation factor b(p-TEFb),Ser2-phosphorylated RNA PolⅡ(RNA PolⅡSer2P),and Ser5-phosphorylated RNA PolⅡ(RNA PolⅡSer5 P).Furthermore,depletion of Npac disrupts transcriptional elongation of the pluripotency genes Nanog and Rif1.Taken together,we propose that Npac is essential for the transcriptional elongation of pluripotency genes by recruiting p-TEFb and interacting with RNA PolⅡSer2P and Ser5P.展开更多
SEL1L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins.However,it remains unclear how SEL1L regula...SEL1L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins.However,it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis.Herein,we found that SEL1L deficiency led to a greatly reduced frequency and number of mature T cells,which was further validated by adoptive transfer experiments or bone marrow chimera experiments,accompanied by the induction of multiple forms of cell death.Furthermore,SEL1L deficiency selectively disrupted naïve CD8+T-cell homeostasis,as indicated by the severe loss of the naïve T-cell subset but an increase in the memory T-cell subset.We also found that SEL1L deficiency fueled mTORC1/c-MYC activation and induced a metabolic shift,which was largely attributable to enhanced expression of the IL-15 receptorαandβchains.Mechanistically,single-cell transcriptomic profiling and biochemical analyses further revealed that Sel1l−/−CD8+T cells harbored excessive ER stress,particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway,which was alleviated by supplementing IL-7 or IL-15.Importantly,PERK inhibition greatly resolved the survival defects of Sel1l−/−CD8+T cells.In addition,IRE1αdeficiency decreased mTORC1 signaling in Sel1l−/−naïve CD8+T cells by downregulating the IL-15 receptorαchain.Altogether,these observations suggest that the ERAD adaptor molecule SEL1L acts as an important checkpoint for preserving the survival and homeostasis of peripheral T cells by regulating the PERK signaling cascade and IL-15 receptor-mediated mTORC1 axis.展开更多
基金supported by the Natural Science Foundation of Jiangsu Province,China(No.BK20241919 to W.H.)the National Natural Science Foundation of China(No.31971062 to W.H.)+2 种基金the Health Promotion Project(China)(No.BJHA-CRP-084 to J.Z.)supported by the Senior Talent Research Program of“Western Medicine learning Traditional Chinese Medicine”in Jiangsu Province,China(to J.Z.)the International Joint Research Center for Genomic Resources(China)(No.2017B01012).
文摘The circadian rhythm,a 24-h cycle,plays a crucial role in regulating gut physiological processes,particularly the proliferation and differentiation of intestinal epithelial cells,which are essential for gut homeostasis and repair.This review discusses the complex interactions between circadian rhythms,cell cycle regulation,and key signaling pathways(Wnt,Notch,and Hippo)in the context of the intestinal stem cell niche and epithelial cell fate decisions.Key molecules such as brain and muscle ARNT-like 1(BMAL1),circadian locomotor output cycles kaput(CLOCK),hairy and enhancer of split 1(Hes1),and Yes-associated protein/transcriptional coactivator with PDZ-binding motif(YAP/TAZ)coordinate stem cell functions with circadian rhythms.We discuss how Notch signaling regulates the cell cycle and interacts with circadian rhythms.Additionally,we explore the role of Hippo-Wnt signaling in balancing cell proliferation and differentiation.Furthermore,we highlight the intricate relationships between circadian clock components and signaling pathways,emphasizing the importance of temporal coordination in determining epithelial cell fate.We also discuss shared enzymes,including casein kinase 1 delta(CK1δ),glycogen synthase kinase 3(GSK3),and AMP-activated protein kinase(AMPK),which play a role in regulating the cell cycle,circadian rhythm,and signaling pathways.In summary,this review offers valuable insights into the regulatory mechanisms that control stem cell behavior and epithelial cell differentiation,suggesting promising directions for future research in intestinal biology and tissue homeostasis.
基金supported by the National Natural Science Foundation of China (31771299 to Dejing Pan)
文摘The announcement of the Nobel Prize in Physiology or Medicine 2017 gave us a mixture of excitement and surprise.Although researchers in circadian rhythm community have been expecting this from the committee of Nobel Prize for quite a few years, several people had guessed that the Nobel Prize in Medicine this year would go to some scientists who discovered immune checkpoints or to those who developed gene editing tools. The Nobel Prize laureate is generally considered as a positive hero in modern science.
基金supported by grants from the National Natural Science Foundation of China(No.31630091 awarded to Ying Xu,No.81600380 awarded to F.Z.,No.31600958 awarded to Z.L.)National Center for International Research(No.2017B01012)
文摘Purpose:Individual chronotypes are reported to be closely associated with mood,health status,and even disease progression.However,no reports of chronotype distribution in the Chinese population have been made available to date.Methods:We performed a chronotype survey using the classic Morningness–Eveningness Questionnaire both online and offline.The webpage-based online survey was distributed via a social network application on mobile phones.The offline survey was distributed to local primary and middle schools.A total of 9476 questionnaires were collected,of which 8395 were valid.The mean age of the participants was 30.38±11.47 years,and 37.38%were male.Results:Overall,the Chinese chronotypes showed a near-normal distribution with a slight shift toward eveningness.When analyzed in different age groups,the overall Chinese population was shown to be"latest"in their early twenties.In the young population,two significant points of change in chronotype were identified at the ages of 10 and 16 years.The chronotype composition remained relatively stable during early adulthood(from 17 to 28 years of age).Conclusion:This study generated the first overview of chronotype distribution in the Chinese population and will serve as essential background data for future studies.
基金supported by Singapore National Medical Research Council(Grant No.CBRG14nov065)the Macao Science and Technology Development Fund,China(Grant No.FDCT-18-033-SKL-016A)。
文摘Chromatin modification contributes to pluripotency maintenance in embryonic stem cells(ESCs).However,the related mechanisms remain obscure.Here,we show that Npac,a"reader"of histone H3 lysine 36 trimethylation(H3K36me3),is required to maintain mouse ESC(mESC)pluripotency since knockdown of Npac causes mESC differentiation.Depletion of Npac in mouse embryonic fibroblasts(MEFs)inhibits reprogramming efficiency.Furthermore,our chromatin immunoprecipitation followed by sequencing(ChIP-seq)results of Npac reveal that Npac co-localizes with histone H3K36me3 in gene bodies of actively transcribed genes in mESCs.Interestingly,we find that Npac interacts with positive transcription elongation factor b(p-TEFb),Ser2-phosphorylated RNA PolⅡ(RNA PolⅡSer2P),and Ser5-phosphorylated RNA PolⅡ(RNA PolⅡSer5 P).Furthermore,depletion of Npac disrupts transcriptional elongation of the pluripotency genes Nanog and Rif1.Taken together,we propose that Npac is essential for the transcriptional elongation of pluripotency genes by recruiting p-TEFb and interacting with RNA PolⅡSer2P and Ser5P.
基金supported by the National Key R&D Program of China(2022YFA0807300)the National Natural Science Foundation of China(82271775 and 81971466)+1 种基金the Natural Science Foundation Outstanding Youth Fund of Jiangsu Province(BK20220049)and the CAMS Innovation Fund for Medical Sciences(CIFMS 2021-I2M-1-061,2021-I2M-1-047 and 2022-I2M-2-004).BZ was in part supported by the Innovation Capability Support Program of Shaanxi 2021TD-38.JZ was in part supported by a Translational Research Grant of NCRCH(2020ZKZC04)and the National Natural Science Foundation of China(82071765)supported by the Natural Science Foundation of China(NSFC 31900645).We thank Prof.Yonghong Wan from McMaster University,Canada,for his critical reading of the manuscript and helpful discussions.
文摘SEL1L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins.However,it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis.Herein,we found that SEL1L deficiency led to a greatly reduced frequency and number of mature T cells,which was further validated by adoptive transfer experiments or bone marrow chimera experiments,accompanied by the induction of multiple forms of cell death.Furthermore,SEL1L deficiency selectively disrupted naïve CD8+T-cell homeostasis,as indicated by the severe loss of the naïve T-cell subset but an increase in the memory T-cell subset.We also found that SEL1L deficiency fueled mTORC1/c-MYC activation and induced a metabolic shift,which was largely attributable to enhanced expression of the IL-15 receptorαandβchains.Mechanistically,single-cell transcriptomic profiling and biochemical analyses further revealed that Sel1l−/−CD8+T cells harbored excessive ER stress,particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway,which was alleviated by supplementing IL-7 or IL-15.Importantly,PERK inhibition greatly resolved the survival defects of Sel1l−/−CD8+T cells.In addition,IRE1αdeficiency decreased mTORC1 signaling in Sel1l−/−naïve CD8+T cells by downregulating the IL-15 receptorαchain.Altogether,these observations suggest that the ERAD adaptor molecule SEL1L acts as an important checkpoint for preserving the survival and homeostasis of peripheral T cells by regulating the PERK signaling cascade and IL-15 receptor-mediated mTORC1 axis.
