One case of acute megakaryoblastic leukemia （AMKL） with trisomy 21,trisomy 14 and unmutated GATA1 gene in a phenotypically normal girl was reported.The patient experienced transient myelodysplasia before the onset o...One case of acute megakaryoblastic leukemia （AMKL） with trisomy 21,trisomy 14 and unmutated GATA1 gene in a phenotypically normal girl was reported.The patient experienced transient myelodysplasia before the onset of AMKL.The bone marrow blasts manifested typical morphology of megakaryoblast both by the May-Giemsa staining and under the electronic microscopy.Leukemic cells were positive for CD13,CD33,CD117,CD56,CD38,CD41 and CD61 in flow cytometry analysis.Cytogenetic study showed karyotype of 48,XX,＋14,＋21 in 40% metaphases.Known mutations of GATA1 gene in Down syndrome or acquired trisomy 21 were not detected in this case.展开更多
Irritable bowel syndrome is a gastrointestinal disorder of unknown etiology characterized by widespread,chronic abdominal pain associated with altered bowel movements.Increasing amounts of evidence indicate that injur...Irritable bowel syndrome is a gastrointestinal disorder of unknown etiology characterized by widespread,chronic abdominal pain associated with altered bowel movements.Increasing amounts of evidence indicate that injury and inflammation during the neonatal period have long-term effects on tissue structure and function in the adult that may predispose to gastrointestinal diseases.In this study we aimed to investigate how the epigenetic regulation of DNA demethylation of the p2x7r locus guided by the transcription factor GATA binding protein 1(GATA1)in spinal astrocytes affects chronic visceral pain in adult rats with neonatal colonic inflammation(NCI).The spinal GATA1 targeting to DNA demethylation of p2x7r locus in these rats was assessed by assessing GATA1 function with luciferase assay,chromatin immunoprecipitation,patch clamp,and interference in vitro and in vivo.In addition,a decoy oligodeoxynucleotide was designed and applied to determine the influence of GATA1 on the DNA methylation of a p2x7r CpG island.We showed that NCI caused the induction of GATA1,Ten-eleven translocation 3(TET3),and purinergic receptors(P2X7Rs)in astrocytes of the spinal dorsal horn,and demonstrated that inhibiting these molecules markedly increased the pain threshold,inhibited the activation of astrocytes,and decreased the spinal sEPSC frequency.NCI also markedly demethylated the p2x7r locus in a manner dependent on the enhancement of both a GATA1–TET3 physical interaction and GATA1 binding at the p2x7r promoter.Importantly,we showed that demethylation of the p2x7r locus(and the attendant increase in P2X7R expression)was reversed upon knockdown of GATA1 or TET3 expression,and demonstrated that a decoy oligodeoxynucleotide that selectively blocked the GATA1 binding site increased the methylation of a CpG island in the p2x7r promoter.These results demonstrate that chronic visceral pain is mediated synergistically by GATA1 and TET3 via a DNA-demethylation mechanism that controls p2x7r transcription in spinal dorsal horn astrocytes,and provide a potential therapeutic strategy by targeting GATA1 and p2x7r locus binding.展开更多
文摘One case of acute megakaryoblastic leukemia （AMKL） with trisomy 21,trisomy 14 and unmutated GATA1 gene in a phenotypically normal girl was reported.The patient experienced transient myelodysplasia before the onset of AMKL.The bone marrow blasts manifested typical morphology of megakaryoblast both by the May-Giemsa staining and under the electronic microscopy.Leukemic cells were positive for CD13,CD33,CD117,CD56,CD38,CD41 and CD61 in flow cytometry analysis.Cytogenetic study showed karyotype of 48,XX,＋14,＋21 in 40% metaphases.Known mutations of GATA1 gene in Down syndrome or acquired trisomy 21 were not detected in this case.
基金supported by grants from National Natural Science Foundation of China(81801115,31730040,and 81920108016)the Priority Academic Program Development of Jiangsu Higher Education Institutions of China,and the China Postdoctoral Science Foundation(2018M642304).
文摘Irritable bowel syndrome is a gastrointestinal disorder of unknown etiology characterized by widespread,chronic abdominal pain associated with altered bowel movements.Increasing amounts of evidence indicate that injury and inflammation during the neonatal period have long-term effects on tissue structure and function in the adult that may predispose to gastrointestinal diseases.In this study we aimed to investigate how the epigenetic regulation of DNA demethylation of the p2x7r locus guided by the transcription factor GATA binding protein 1(GATA1)in spinal astrocytes affects chronic visceral pain in adult rats with neonatal colonic inflammation(NCI).The spinal GATA1 targeting to DNA demethylation of p2x7r locus in these rats was assessed by assessing GATA1 function with luciferase assay,chromatin immunoprecipitation,patch clamp,and interference in vitro and in vivo.In addition,a decoy oligodeoxynucleotide was designed and applied to determine the influence of GATA1 on the DNA methylation of a p2x7r CpG island.We showed that NCI caused the induction of GATA1,Ten-eleven translocation 3(TET3),and purinergic receptors(P2X7Rs)in astrocytes of the spinal dorsal horn,and demonstrated that inhibiting these molecules markedly increased the pain threshold,inhibited the activation of astrocytes,and decreased the spinal sEPSC frequency.NCI also markedly demethylated the p2x7r locus in a manner dependent on the enhancement of both a GATA1–TET3 physical interaction and GATA1 binding at the p2x7r promoter.Importantly,we showed that demethylation of the p2x7r locus(and the attendant increase in P2X7R expression)was reversed upon knockdown of GATA1 or TET3 expression,and demonstrated that a decoy oligodeoxynucleotide that selectively blocked the GATA1 binding site increased the methylation of a CpG island in the p2x7r promoter.These results demonstrate that chronic visceral pain is mediated synergistically by GATA1 and TET3 via a DNA-demethylation mechanism that controls p2x7r transcription in spinal dorsal horn astrocytes,and provide a potential therapeutic strategy by targeting GATA1 and p2x7r locus binding.
