Comparative epigenomics of human and mouse erythropoiesis
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ABSTRACT:
PROVIDER: PRJNA256270 | ENA |
REPOSITORIES: ENA
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Project description:Erythropoiesis is one of the best understood examples of cellular differentiation. Morphologically, erythroid differentiation proceeds in a nearly identical fashion between humans and mice, but recent evidence has shown that networks of gene expression governing this process are divergent between species. We undertook a systematic comparative analysis of six histone modifications and four transcriptional master regulators in primary pro-erythroblasts and erythroid cell lines to better understand the underlying basis of these transcriptional differences. Our analyses suggest that while chromatin structure across orthologous promoters is strongly conserved, subtle differences are associated with transcriptional divergence between species. Many transcription factor (TF) occupancy sites were poorly conserved across species (~25% for GATA1, TAL1, and NFE2), but these factors were considerably more conserved between proerythroblasts and cell lines derived from the same species. We found that certain cis-regulatory modules co-occupied by GATA1, TAL1, and KLF1 are under strict evolutionary constraint and localize to genes necessary for erythroid cell identity. More generally, we show that conserved TF occupancy sites are indicative of active regulatory regions and strong gene expression sustained during maturation. Our results suggest that evolutionary turnover of TF binding sites drives transcriptional divergence partially by mediating changes in the underlying chromatin structure. We provide examples of how this framework can be applied to understand epigenomic variation in specific regulatory regions, such as the Beta-globin gene locus. Our findings have important implications for understanding epigenomic changes that mediate variation in cellular differentiation across species, while also providing a valuable resource for studies of hematopoiesis.
2014-12-01 | GSE59801 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE36984: Expression Profiling of Primary Human Fetal and Adult Hematopoietic Stem/Progenitor Cells (HSPCs) and Differentiating Proerythroblasts (ProEs) GSE36985: Comparative profiling of chromatin state maps and transcription factor occupancy during human fetal and adult erythropoiesis GSE36988: Expression Profiling of Primary Human Proerythroblasts (ProEs) After IRF2, IRF6, and MYB shRNA Knockdown Refer to individual Series
2012-10-04 | E-GEOD-36994 | biostudies-arrayexpress
Project description:We report the comparative investigation of genome-wide chromatin state maps, transcription factor (TF) occupancy, and gene expression profiles from developing red cell precursors at two developmental stages. Contrasting the similarities and differences between fetal and adult erythropoiesis provides important insights into the erythroid gene expression programs and gene regulatory networks. Specifically, comparative analyses of human erythropoiesis identify developmental stage-specific enhancers as primary determinants of stage-specific gene expression programs. We find that master regulators, such as GATA1 and TAL1, cooperatively act within active enhancers but have little predictive value for stage-specific enhancer activity. Instead, a set of stage-specific co-regulators collaborates with master regulators and contributes to differential gene expression. We further identify and validate IRF2, IRF6, and MYB as effectors of adult-stage expression program. Thus, the combinatorial assembly of master regulators and transcriptional co-regulators at developmental stage-specific enhancers controls gene expression programs and temporal regulation of transcriptional networks in a mammalian genome. Examination of various histone modifications and transcription factor occupancy by ChIP-seq in fetal and adult proerythroblasts.
2012-10-05 | E-GEOD-36985 | biostudies-arrayexpress
Project description:Gene silencing by aberrant epigenetic chromatin alteration is a well-recognized event contributing to tumorigenesis. Although genetically engineered tumor-prone mouse models have proven a powerful tool in understanding many aspects of carcinogenesis, to date few studies have focused on epigenetic alterations in mouse tumors. To uncover epigenetically silenced tumor suppressor genes (TSGs) in mouse mammary tumor cells, we conducted initial genome-wide screening by combining the treatment of cultured cells with the DNA demethylating drug 5-aza-2'-deoxycytidine (5-azadC) and the histone deacetylase inhibitor trichostatin A (TSA) with expression microarray. By conducting this initial screen on EMT6 cells and applying protein function and genomic structure criteria to genes identified as upregulated in response to 5-azadC/TSA, we were able to identify two characterized breast cancer TSGs (Timp3 and Rprm) and four putative TSGs (Atp1B2, Dusp2, FoxJ1 and Smpd3) silenced in this line. By testing a panel of 10 mouse mammary tumor lines, we determined that each of these genes is commonly hypermethylated, albeit with varying frequency. Furthermore, by examining a panel of human breast tumor lines and primary tumors we observed that the human orthologs of ATP1B2, FOXJ1 and SMPD3 are aberrantly hypermethylated in the human disease whereas DUSP2 was not hypermethylated in primary breast tumors. Finally, we examined hypermethylation of several genes targeted for epigenetic silencing in human breast tumors in our panel of 10 mouse mammary tumor lines. We observed that the orthologs of Cdh1, RarB, Gstp1, RassF1 genes were hypermethylated, whereas neither Dapk1 nor Wif1 were aberrantly methylated in this panel of mouse tumor lines. From this study, we conclude that there is significant, but not absolute, overlap in the epigenome of human and mouse mammary tumors.
| S-EPMC2929596 | biostudies-literature
Project description:We report the comparative investigation of genome-wide chromatin state maps, transcription factor (TF) occupancy, and gene expression profiles from developing red cell precursors at two developmental stages. Contrasting the similarities and differences between fetal and adult erythropoiesis provides important insights into the erythroid gene expression programs and gene regulatory networks. Specifically, comparative analyses of human erythropoiesis identify developmental stage-specific enhancers as primary determinants of stage-specific gene expression programs. We find that master regulators, such as GATA1 and TAL1, cooperatively act within active enhancers but have little predictive value for stage-specific enhancer activity. Instead, a set of stage-specific co-regulators collaborates with master regulators and contributes to differential gene expression. We further identify and validate IRF2, IRF6, and MYB as effectors of adult-stage expression program. Thus, the combinatorial assembly of master regulators and transcriptional co-regulators at developmental stage-specific enhancers controls gene expression programs and temporal regulation of transcriptional networks in a mammalian genome.
2012-10-05 | GSE36985 | GEO
Project description:Transcriptomics of mouse bone marrow erythropoiesis
| PRJNA938477 | ENA
Project description:We performed a proteomic analysis of human erythropoiesis using 4 umbilical cord's blood samples. This study revealed the absolute and quantitative expression of more than 6000 proteins throughout 7 stages of erythroid differentiation using a label-free technique. We found new informations on erythropoiesis such as unexpected protein expression depicted the article.
2016-08-08 | PXD004313 | Pride
Project description:Immunodeficient mouse models have been valuable for studies of human hematopoiesis, but high-fidelity recapitulation of erythropoiesis in most xenograft recipients remains elusive. Recently developed immunodeficient and Kit mutant mice, however, have provided a suitable background to achieve higher-level human erythropoiesis after long-term hematopoietic engraftment. While there has been some characterization of human erythropoiesis in these models, a comprehensive analysis of various developmental stages has not yet been reported. Here, we have utilized cell surface phenotypes, morphologic analyses, and molecular studies to fully characterize human erythropoiesis from multiple developmental stages in immunodeficient and Kit mutant mouse models following long-term hematopoietic stem and progenitor cell engraftment. We show that human erythropoiesis in such models demonstrates complete maturation and enucleation, as well as developmentally appropriate globin gene expression. These results provide a framework for future studies to utilize this model system for interrogating disorders affecting human erythropoiesis and for developing improved therapeutic approaches.
2017-06-16 | GSE100077 | GEO
Project description:Studies of human erythropoiesis have relied, for the most part, on the in vitro differentiation of hematopoietic stem and progenitor cells (HSPC) from different sources. Here, we report that despite the common core erythroid program that exists between cord blood- and peripheral blood-HSPC induced towards erythroid differentiation in vitro, significant functional differences exist. We undertook a comparative analysis of human erythropoiesis using these two different sources of HSPC and differentiated them in vitro. We observed that cells derived from cord blood proliferate 4.5 times more than cells derived from peripheral blood. However, these cells present a delay in their differentiation pattern due to increased quantities of progenitors, notably CFU-E. Using our method of immunophenotyping for the study of erythroid progenitors, we document the presence and maintenance of a specific population in peripheral blood-derived erythroid progenitors. This population, defined as IL3R-GPA-CD34+CD36+, has the ability to form both BFU-E and CFU-E colonies in colony-forming assays, reflecting a higher potential. To further understand the differences between cord blood- and peripheral blood- HSPC, we sorted all stages of erythropoiesis from both sources and compared their transcriptome. We document differences at the CD34, BFU-E, poly- and orthochromatic stages. Among the genes presenting the highest differences in expression, many are involved in the regulation of the cell cycle and autophagy. Altogether, our studies provide a qualitative and quantitative comparative analysis of human erythropoiesis and highlight functional differences, critical to our understanding of the impact of the developmental origin of HSPCs on erythroid differentiation.
2017-12-28 | GSE107218 | GEO
Project description:We performed a proteomic analysis of human erythropoiesis using 4 umbilical cord's blood samples. This study revealed the absolute and quantitative expression of more than 6000 proteins throughout 7 stages of erythroid differentiation using a label-free technique. We found new informations on erythropoiesis such as unexpected protein expression depicted the article.
2016-08-08 | PXD004314 | Pride