Non-coding cis-regulatory elements(CREs),such as transcriptional enhancers,are key regulators of gene expression programs.Accessible chromatin and H3K27ac are well-recognized markers for CREs associated with their bio...Non-coding cis-regulatory elements(CREs),such as transcriptional enhancers,are key regulators of gene expression programs.Accessible chromatin and H3K27ac are well-recognized markers for CREs associated with their biological function.Deregulation of CREs is commonly found in hematopoietic malignancies,yet the extent to which CRE dysfunction contributes to pathophysiology remains incompletely understood.Here,we developed HemaCisDB,an interactive,comprehensive,and centralized online resource for CRE characterization across hematopoietic malignancies,serving as a useful resource for investigating the pathological roles of CREs in blood disorders.Currently,we collected 922 assay of transposase accessible chromatin with sequencing(ATAC-seq),190 DNase I hypersensitive site sequencing(DNase-seq),and 531 H3K27ac chromatin immunoprecipitation followed by sequencing(ChIP-seq)datasets from patient samples and cell lines across different myeloid and lymphoid neoplasms.HemaCisDB provides comprehensive quality control metrics to assess ATAC-seq,DNase-seq,and H3K27ac ChIP-seq data quality.The analytic modules in HemaCisDB include transcription factor(TF)footprinting inference,super-enhancer identification,and core transcriptional regulatory circuitry analysis.Moreover,HemaCisDB also enables the study of TF binding dynamics by comparing TF footprints across different disease types or conditions via web-based interactive analysis.Together,HemaCisDB provides an interactive platform for CRE characterization to facilitate mechanistic studies of transcriptional regulation in hematopoietic malignancies.HemaCisDB is available at https://hemacisdb.chinablood.com.cn/.展开更多
The aryl hydrocarbon receptor(AHR)plays an important role during mammalian embryo development.Inhibition of AHR signaling promotes the development of hematopoietic stem/progenitor cells.AHR also regulates the function...The aryl hydrocarbon receptor(AHR)plays an important role during mammalian embryo development.Inhibition of AHR signaling promotes the development of hematopoietic stem/progenitor cells.AHR also regulates the functional maturation of blood cells,such as T cells and megakaryocytes.However,little is known about the role of AHR modulation during the development of erythroid cells.In this study,we used the AHR antagonist StemRegenin 1(SR1)and the AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin during different stages of human erythropoiesis to elucidate the function of AHR.We found that antagonizing AHR signaling improved the production of human embryonic stem cell derived erythrocytes and enhanced erythroid terminal differentiation.RNA sequencing showed that SR1 treatment of proerythroblasts upregulated the expression of erythrocyte differentiation-related genes and downregulated actin organization-associated genes.We found that SR1 accelerated F-actin remodeling in terminally differentiated erythrocytes,favoring their maturation of the cytoskeleton and enucleation.We demonstrated that the effects of AHR inhibition on erythroid maturation were associated with F-actin remodeling.Our findings help uncover the mechanism for AHRmediated human erythroid cell differentiation.We also provide a new approach toward the large-scale production of functionally mature human pluripotent stem cell-derived erythrocytes for use in translational applications.展开更多
基金supported by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(Grant No.2022-RC310-03)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS)(Grant No.2022-I2M-1-022)+1 种基金the State Key Laboratory of Experimental Hematology Research Grant(Grant No.Z22-01)the Biomedical High Performance Computing Platform,Chinese Academy of Medical Sciences.
文摘Non-coding cis-regulatory elements(CREs),such as transcriptional enhancers,are key regulators of gene expression programs.Accessible chromatin and H3K27ac are well-recognized markers for CREs associated with their biological function.Deregulation of CREs is commonly found in hematopoietic malignancies,yet the extent to which CRE dysfunction contributes to pathophysiology remains incompletely understood.Here,we developed HemaCisDB,an interactive,comprehensive,and centralized online resource for CRE characterization across hematopoietic malignancies,serving as a useful resource for investigating the pathological roles of CREs in blood disorders.Currently,we collected 922 assay of transposase accessible chromatin with sequencing(ATAC-seq),190 DNase I hypersensitive site sequencing(DNase-seq),and 531 H3K27ac chromatin immunoprecipitation followed by sequencing(ChIP-seq)datasets from patient samples and cell lines across different myeloid and lymphoid neoplasms.HemaCisDB provides comprehensive quality control metrics to assess ATAC-seq,DNase-seq,and H3K27ac ChIP-seq data quality.The analytic modules in HemaCisDB include transcription factor(TF)footprinting inference,super-enhancer identification,and core transcriptional regulatory circuitry analysis.Moreover,HemaCisDB also enables the study of TF binding dynamics by comparing TF footprints across different disease types or conditions via web-based interactive analysis.Together,HemaCisDB provides an interactive platform for CRE characterization to facilitate mechanistic studies of transcriptional regulation in hematopoietic malignancies.HemaCisDB is available at https://hemacisdb.chinablood.com.cn/.
基金supported by the National Basic Research Program(973 Program,2015CB964902)the National Natural Science Foundation of China(H81170466 and H81370597)the CAMS Initiatives for Innovative Medicine(2016-I2M-1-018,2019-I2M-1-006,and 2017-I2M-2005)to F.M.,the National Natural Science Foundation of China Youth Fund(82000119)to Yonggang Zhang.
文摘The aryl hydrocarbon receptor(AHR)plays an important role during mammalian embryo development.Inhibition of AHR signaling promotes the development of hematopoietic stem/progenitor cells.AHR also regulates the functional maturation of blood cells,such as T cells and megakaryocytes.However,little is known about the role of AHR modulation during the development of erythroid cells.In this study,we used the AHR antagonist StemRegenin 1(SR1)and the AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin during different stages of human erythropoiesis to elucidate the function of AHR.We found that antagonizing AHR signaling improved the production of human embryonic stem cell derived erythrocytes and enhanced erythroid terminal differentiation.RNA sequencing showed that SR1 treatment of proerythroblasts upregulated the expression of erythrocyte differentiation-related genes and downregulated actin organization-associated genes.We found that SR1 accelerated F-actin remodeling in terminally differentiated erythrocytes,favoring their maturation of the cytoskeleton and enucleation.We demonstrated that the effects of AHR inhibition on erythroid maturation were associated with F-actin remodeling.Our findings help uncover the mechanism for AHRmediated human erythroid cell differentiation.We also provide a new approach toward the large-scale production of functionally mature human pluripotent stem cell-derived erythrocytes for use in translational applications.
