Polycystic ovary syndrome(PCOS)is a frequent endocrine and metabolic imbalance that typically occurs in women of reproductive age.Its molecular pathophysiology is yet unknown,especially the ovarian cellular metabolic ...Polycystic ovary syndrome(PCOS)is a frequent endocrine and metabolic imbalance that typically occurs in women of reproductive age.Its molecular pathophysiology is yet unknown,especially the ovarian cellular metabolic inefficiency that causes the transcriptional dysregulation of key genes linked to PCOS.Here,we discovered that one transcriptional-like regulator that causes PCOS is nuclear pyruvate kinase M2(nPKM2).Using multiomics techniques,we show that enhanced lactylation of histone 3 on lysine residues 9 and 18 is linked to nPKM2 binding to the genome,changing the three-dimensional architecture of the genome.Genomic compartment switching,topologically associated domain fusion,and novel enhancer–promoter interactions subsequently enhance the expression of PCOS-related genes,including CYP17A1 and CYP11A1.In mice,ectopic expression of Pkm2 in female GCs consistently presented PCOS-like traits,such as interrupted estrous cycles,hyperandrogenism,and so on.Importantly,whole-organ tracing imaging directly unfolded the number of small follicles,which increased highly in Pkm2-tdtomato transgene mice compared with control.Furthermore,pharmacological inhibition of the nuclear accumulation of PKM2 mitigated PCOS-like symptoms in mice and restored a wild-type-like transcriptome.This study demonstrates the important function of PKM2-mediated histone lactylation in regulating the three-dimensional chromatin architecture and highlights PKM2 as a potential therapeutic target for PCOS treatment.展开更多
Dear Editor,Recurrent pregnancy loss (RPL) in early pregnancy is a devastating problem for couples who want to become parents and a difficult challenge for their physician.RPL is also referred to as recurrent miscarri...Dear Editor,Recurrent pregnancy loss (RPL) in early pregnancy is a devastating problem for couples who want to become parents and a difficult challenge for their physician.RPL is also referred to as recurrent miscarriage or habitual abortion.It is defined as two or more consecutive clinical miscarriages (CMs) before 20 weeks of gestation (Practice Committee of the American Society for Reproductive Medicine,2012).展开更多
Dear Editor, Intracellular trafficking is a basis of cellular activities, including cell migration, immune response, and development （Lebreton et al., 2003; Lu（;in et al., 2014; Ulrich and Heisenberg, 2009）. In hea...Dear Editor, Intracellular trafficking is a basis of cellular activities, including cell migration, immune response, and development （Lebreton et al., 2003; Lu（;in et al., 2014; Ulrich and Heisenberg, 2009）. In healthy tissue, intracellular trafficking is highly regulated, con- trolling the form and function of cells （Furthauer and Gonzalez- Gaitan, 2009）.展开更多
基金supported by the Medical Science Data Center of Fudan University and the Big Data Computing Center of Southeast University.We thank the National Natural Science Foundation of China(82088102,82271669,and 81671412)the National Key Research and Development Program of China(2022YFC2703600)+7 种基金the International Cooperation Project of China and Canada NSFC(81661128010)the Collaborative Innovation Program of Shanghai Municipal Health Commission(2020CXJQ01)the Key Discipline Construction Project(2023-2025)of the Three-Year Initiative Plan for Strengthening Public Health System Construction in Shanghai(GWVI-11.1-35)the Clinical Research Plan of SHDC(SHDC2020CR1008A)the Shanghai Clinical Research Center for Gynecological Diseases(22MC1940200)the Shanghai Urogenital System Diseases Research Center(2022ZZ01012)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-064)the Shanghai Frontiers Science Research Center of Reproduction and Development.Postdoctoral grant(2018M630454)。
文摘Polycystic ovary syndrome(PCOS)is a frequent endocrine and metabolic imbalance that typically occurs in women of reproductive age.Its molecular pathophysiology is yet unknown,especially the ovarian cellular metabolic inefficiency that causes the transcriptional dysregulation of key genes linked to PCOS.Here,we discovered that one transcriptional-like regulator that causes PCOS is nuclear pyruvate kinase M2(nPKM2).Using multiomics techniques,we show that enhanced lactylation of histone 3 on lysine residues 9 and 18 is linked to nPKM2 binding to the genome,changing the three-dimensional architecture of the genome.Genomic compartment switching,topologically associated domain fusion,and novel enhancer–promoter interactions subsequently enhance the expression of PCOS-related genes,including CYP17A1 and CYP11A1.In mice,ectopic expression of Pkm2 in female GCs consistently presented PCOS-like traits,such as interrupted estrous cycles,hyperandrogenism,and so on.Importantly,whole-organ tracing imaging directly unfolded the number of small follicles,which increased highly in Pkm2-tdtomato transgene mice compared with control.Furthermore,pharmacological inhibition of the nuclear accumulation of PKM2 mitigated PCOS-like symptoms in mice and restored a wild-type-like transcriptome.This study demonstrates the important function of PKM2-mediated histone lactylation in regulating the three-dimensional chromatin architecture and highlights PKM2 as a potential therapeutic target for PCOS treatment.
基金supported by the major program of the National Natural Science Foundation of China(81671456 to X.M.L,81490742 to H.F.H.)the Science and Technology 332 Commission of Shanghai(14DJ1400100 to H.F.H.)+2 种基金the International Peace Maternity and Child Health Hospital Support Program(Y.T.T.)the Medical and Health Science and Technology Plan of Zhejiang Province(2017KY078 to C.F.)the Science and Technology Projects of Competent Departments(2017FZA7013 to P.P.L)
文摘Dear Editor,Recurrent pregnancy loss (RPL) in early pregnancy is a devastating problem for couples who want to become parents and a difficult challenge for their physician.RPL is also referred to as recurrent miscarriage or habitual abortion.It is defined as two or more consecutive clinical miscarriages (CMs) before 20 weeks of gestation (Practice Committee of the American Society for Reproductive Medicine,2012).
基金This work was supported by grants from the National Natural Sci- ence Foundation （Grant No. 31270884）, the Beijing Natural Science Foundation （5122026）, and Youth Innovation Promotion Association, Chinese Academy of Sciences.
文摘Dear Editor, Intracellular trafficking is a basis of cellular activities, including cell migration, immune response, and development （Lebreton et al., 2003; Lu（;in et al., 2014; Ulrich and Heisenberg, 2009）. In healthy tissue, intracellular trafficking is highly regulated, con- trolling the form and function of cells （Furthauer and Gonzalez- Gaitan, 2009）.
