Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA192979 | ENA |
REPOSITORIES: ENA
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Project description:Earlier work demonstrated that the transcription factor C/EBPα can convert immature and mature murine B lineage cells into functional macrophages. Testing >20 human lymphoma and leukemia B-cell lines, we found that most can be transdifferentiated at least partially into macrophage-like cells, provided that C/EBPα is expressed at sufficiently high levels. A tamoxifen-inducible subclone of the Seraphina Burkitt lymphoma line, expressing C/EBPαER, could be efficiently converted into phagocytic and quiescent cells with a transcriptome resembling normal macrophages. The converted cells retained their phenotype even when C/EBPα was inactivated, a hallmark of cell reprogramming. Interestingly, C/EBPα induction also impaired the cells' tumorigenicity. Likewise, C/EBPα efficiently converted a B- lymphoblastic leukemia cell line into macrophage-like cells, again dramatically impairing their tumorigenicity. Our experiments show that human cancer cells can be induced to transdifferentiate by C/EBPα into seemingly normal cells at high frequencies and provide a proof of principle for a potential new therapeutic strategy to treat B-cell malignancies.
2013-03-14 | GSE44700 | GEO
Project description:C/EBPα induces transdifferentiation of B cells into macrophages at high efficiencies and enhances reprogramming into induced pluripotent stem cells (iPSCs) when co-expressed with Oct4, Sox2, Klf4 and Myc (OSKM). However, how C/EBPα accomplishes these effects is unclear. We now found that transient C/EBPα expression followed by OSKM activation induces a 100 fold increase in iPSC reprogramming efficiency, involving 95% of the cells. During this conversion pluripotency and epithelial-mesenchymal transition genes become dramatically up-regulated and 60% of the cells express Oct4 within 2 days. C/EBPα acts as a pathbreaker since it transiently makes the chromatin of pluripotency genes more accessible to DNase I. It also induces the expression of the dioxygenase Tet2 and promotes its translocation to the nucleus where it binds to regulatory regions of pluripotency genes that become demethylated following OSKM induction. In line with these findings, overexpression of Tet2 enhances OSKM‐induced B cell reprogramming. Since the enzyme is also required for efficient C/EBPα-induced immune cell conversion, our data suggest that Tet2 provides a mechanistic link between iPSC reprogramming and B cell transdifferentiation. The rapid iPS reprogramming approach described should help to fully elucidate the process and has potential clinical applications. Change in Cebpa genome binding/occupancy, comparing primary B-cells treated with estradiol for 18h to induce C/EBPa to untreated cells.
2013-11-17 | E-GEOD-52373 | biostudies-arrayexpress
Project description:C/EBPα induces transdifferentiation of B cells into macrophages at high efficiencies and enhances reprogramming into induced pluripotent stem cells (iPSCs) when co-expressed with Oct4, Sox2, Klf4 and Myc (OSKM). However, how C/EBPα accomplishes these effects is unclear. We now found that transient C/EBPα expression followed by OSKM activation induces a 100 fold increase in iPSC reprogramming efficiency, involving 95% of the cells. During this conversion pluripotency and epithelial-mesenchymal transition genes become dramatically up-regulated and 60% of the cells express Oct4 within 2 days. C/EBPα acts as a pathbreaker since it transiently makes the chromatin of pluripotency genes more accessible to DNase I. It also induces the expression of the dioxygenase Tet2 and promotes its translocation to the nucleus where it binds to regulatory regions of pluripotency genes that become demethylated following OSKM induction. In line with these findings, overexpression of Tet2 enhances OSKM‐induced B cell reprogramming. Since the enzyme is also required for efficient C/EBPα-induced immune cell conversion, our data suggest that Tet2 provides a mechanistic link between iPSC reprogramming and B cell transdifferentiation. The rapid iPS reprogramming approach described should help to fully elucidate the process and has potential clinical applications.
2013-11-17 | GSE52397 | GEO
Project description:C/EBPα induces transdifferentiation of B cells into macrophages at high efficiencies and enhances reprogramming into induced pluripotent stem cells (iPSCs) when co-expressed with Oct4, Sox2, Klf4 and Myc (OSKM). However, how C/EBPα accomplishes these effects is unclear. We now found that transient C/EBPα expression followed by OSKM activation induces a 100 fold increase in iPSC reprogramming efficiency, involving 95% of the cells. During this conversion pluripotency and epithelial-mesenchymal transition genes become dramatically up-regulated and 60% of the cells express Oct4 within 2 days. C/EBPα acts as a pathbreaker since it transiently makes the chromatin of pluripotency genes more accessible to DNase I. It also induces the expression of the dioxygenase Tet2 and promotes its translocation to the nucleus where it binds to regulatory regions of pluripotency genes that become demethylated following OSKM induction. In line with these findings, overexpression of Tet2 enhances OSKM‐induced B cell reprogramming. Since the enzyme is also required for efficient C/EBPα-induced immune cell conversion, our data suggest that Tet2 provides a mechanistic link between iPSC reprogramming and B cell transdifferentiation. The rapid iPS reprogramming approach described should help to fully elucidate the process and has potential clinical applications.
2013-11-17 | GSE52396 | GEO
Project description:C/EBPα induces transdifferentiation of B cells into macrophages at high efficiencies and enhances reprogramming into induced pluripotent stem cells (iPSCs) when co-expressed with Oct4, Sox2, Klf4 and Myc (OSKM). However, how C/EBPα accomplishes these effects is unclear. We now found that transient C/EBPα expression followed by OSKM activation induces a 100 fold increase in iPSC reprogramming efficiency, involving 95% of the cells. During this conversion pluripotency and epithelial-mesenchymal transition genes become dramatically up-regulated and 60% of the cells express Oct4 within 2 days. C/EBPα acts as a pathbreaker since it transiently makes the chromatin of pluripotency genes more accessible to DNase I. It also induces the expression of the dioxygenase Tet2 and promotes its translocation to the nucleus where it binds to regulatory regions of pluripotency genes that become demethylated following OSKM induction. In line with these findings, overexpression of Tet2 enhances OSKM‐induced B cell reprogramming. Since the enzyme is also required for efficient C/EBPα-induced immune cell conversion, our data suggest that Tet2 provides a mechanistic link between iPSC reprogramming and B cell transdifferentiation. The rapid iPS reprogramming approach described should help to fully elucidate the process and has potential clinical applications.
2013-11-17 | GSE52373 | GEO
Project description:Earlier work demonstrated that the transcription factor C/EBPα can convert immature and mature murine B lineage cells into functional macrophages. Testing >20 human lymphoma and leukemia B-cell lines, we found that most can be transdifferentiated at least partially into macrophage-like cells, provided that C/EBPα is expressed at sufficiently high levels. A tamoxifen-inducible subclone of the Seraphina Burkitt lymphoma line, expressing C/EBPαER, could be efficiently converted into phagocytic and quiescent cells with a transcriptome resembling normal macrophages. The converted cells retained their phenotype even when C/EBPα was inactivated, a hallmark of cell reprogramming. Interestingly, C/EBPα induction also impaired the cells' tumorigenicity. Likewise, C/EBPα efficiently converted a B- lymphoblastic leukemia cell line into macrophage-like cells, again dramatically impairing their tumorigenicity. Our experiments show that human cancer cells can be induced to transdifferentiate by C/EBPα into seemingly normal cells at high frequencies and provide a proof of principle for a potential new therapeutic strategy to treat B-cell malignancies. Changes in gene expression during transdifferentiation of BLaER1 cells, comparing uninduced (0h) cells with cells treated with E2 for 3h, 6h, 9h, 12h, 18h, 24h, 36h, 48h, 72h, 120h or 168h. Primary human B-cells and macrophages were used as controls. 2 replicates each.
2013-03-14 | E-GEOD-44700 | biostudies-arrayexpress
Project description:Somatic cell reprogramming into pluripotent stem cells induced by Oct4, Sox2, Klf4 and Myc (OSKM) occurs at low frequencies and with a considerable delay involving a stochastic phase. In contrast, transdifferentiation of B cells into macrophages induced by C/EBPα is fully efficient and initiated almost immediately. We now discovered that a pulse of C/EBPα in B cell precursors followed by OSKM expression dramatically enhances reprogramming to pluripotency, overcoming the stochastic phase. The cells simultaneously activate mesenchymal-epithelial transition and pluripotency genes to high levels within 2 days, correlating with promoter demethylation and accessibility to Oct4 binding. The conditioning effect of C/EBPα is shared with C/EBPβ but not with transcription factors that induce erythroid, neuronal and muscle fates, which are innocuous or inhibitory. Surprisingly, OSKM induce the transient upregulation of macrophage genes in B cells, including Cebpa and Cebpb, as well as trophectoderm genes. Since both C/EBPs are functionally expressed in trophoblasts their unique pluripotency-conditioning capacity might reflect an early embryonic function. Our findings have removed a major hurdle in elucidating mechanisms that establish pluripotency.
2013-11-17 | GSE46321 | GEO
Project description:C/EBPα is a potent inducer of lymphoid to myeloid cell transdifferentiation. Here we describe that Carm1 methylates arginine 35 in the transactivation domain of C/EBPα, modulating the factor’s activity. Inhibition of methylation or mutation of R35 dramatically enhances the capacity of C/EBPα to induce a B cell-to-macrophage conversion through accelerated chromatin remodeling and subsequent upregulation of myeloid genes and downregulation of B cell genes. This phenomenon is mediated by an increased interaction of unmethylated C/EBPα with the bi-lineage transcription factor PU.1, resulting in the accelerated relocation of PU.1 from B cell to myeloid gene regulatory elements and thus enhancing chromatin remodeling. Our data suggests that C/EBPα effectively converts PU.1 from a B cell to a myeloid regulator through a ‘stealing’ process, and that methylation of C/EBPα by Carm1 modulates this interaction. We propose that individual cells display a pool of methylated and unmethylated C/EBPα, and the proportion of the two molecular forms determines the velocity of cell fate conversion.
2023-07-05 | GSE229072 | GEO
Project description:C/EBPα is a potent inducer of lymphoid to myeloid cell transdifferentiation. Here we describe that Carm1 methylates arginine 35 in the transactivation domain of C/EBPα, modulating the factor’s activity. Inhibition of methylation or mutation of R35 dramatically enhances the capacity of C/EBPα to induce a B cell-to-macrophage conversion through accelerated chromatin remodeling and subsequent upregulation of myeloid genes and downregulation of B cell genes. This phenomenon is mediated by an increased interaction of unmethylated C/EBPα with the bi-lineage transcription factor PU.1, resulting in the accelerated relocation of PU.1 from B cell to myeloid gene regulatory elements and thus enhancing chromatin remodeling. Our data suggests that C/EBPα effectively converts PU.1 from a B cell to a myeloid regulator through a ‘stealing’ process, and that methylation of C/EBPα by Carm1 modulates this interaction. We propose that individual cells display a pool of methylated and unmethylated C/EBPα, and the proportion of the two molecular forms determines the velocity of cell fate conversion.
2023-07-05 | GSE204745 | GEO
Project description:C/EBPα is a potent inducer of lymphoid to myeloid cell transdifferentiation. Here we describe that Carm1 methylates arginine 35 in the transactivation domain of C/EBPα, modulating the factor’s activity. Inhibition of methylation or mutation of R35 dramatically enhances the capacity of C/EBPα to induce a B cell-to-macrophage conversion through accelerated chromatin remodeling and subsequent upregulation of myeloid genes and downregulation of B cell genes. This phenomenon is mediated by an increased interaction of unmethylated C/EBPα with the bi-lineage transcription factor PU.1, resulting in the accelerated relocation of PU.1 from B cell to myeloid gene regulatory elements and thus enhancing chromatin remodeling. Our data suggests that C/EBPα effectively converts PU.1 from a B cell to a myeloid regulator through a ‘stealing’ process, and that methylation of C/EBPα by Carm1 modulates this interaction. We propose that individual cells display a pool of methylated and unmethylated C/EBPα, and the proportion of the two molecular forms determines the velocity of cell fate conversion.
2023-07-05 | GSE204742 | GEO