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- Hosokawa, Hiroyuki, et al.
(författare)
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Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16
- 2018
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Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 19:12, s. 1427-1440
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Tidskriftsartikel (refereegranskat)abstract
- Multipotent progenitor cells confirm their T cell–lineage identity in the CD4–CD8– double-negative (DN) pro-T cell DN2 stages, when expression of the essential transcription factor Bcl11b begins. In vivo and in vitro stage-specific deletions globally identified Bcl11b-controlled target genes in pro-T cells. Proteomics analysis revealed that Bcl11b associated with multiple cofactors and that its direct action was needed to recruit those cofactors to selective target sites. Regions near functionally regulated target genes showed enrichment for those sites of Bcl11b-dependent recruitment of cofactors, and deletion of individual cofactors relieved the repression of many genes normally repressed by Bcl11b. Runx1 collaborated with Bcl11b most frequently for both activation and repression. In parallel, Bcl11b indirectly regulated a subset of target genes by a gene network circuit via the transcription inhibitor Id2 (encoded by Id2) and transcription factor PLZF (encoded by Zbtb16); Id2 and Zbtb16 were directly repressed by Bcl11b, and Id2 and PLZF controlled distinct alternative programs. Thus, our study defines the molecular basis of direct and indirect Bcl11b actions that promote T cell identity and block alternative potentials.
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| 3. |
- Hosokawa, Hiroyuki, et al.
(författare)
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Transcription Factor PU.1 Represses and Activates Gene Expression in Early T Cells by Redirecting Partner Transcription Factor Binding
- 2018
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Ingår i: Immunity. - : Elsevier BV. - 1074-7613. ; 48:6, s. 7-1134
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Tidskriftsartikel (refereegranskat)abstract
- Transcription factors normally regulate gene expression through their action at sites where they bind to DNA. However, the balance of activating and repressive functions that a transcription factor can mediate is not completely understood. Here, we showed that the transcription factor PU.1 regulated gene expression in early T cell development both by recruiting partner transcription factors to its own binding sites and by depleting them from the binding sites that they preferred when PU.1 was absent. The removal of partner factors Satb1 and Runx1 occurred primarily from sites where PU.1 itself did not bind. Genes linked to sites of partner factor “theft” were enriched for genes that PU.1 represses despite lack of binding, both in a model cell line system and in normal T cell development. Thus, system-level competitive recruitment dynamics permit PU.1 to affect gene expression both through its own target sites and through action at a distance. Transcription factors regulate target genes via sequence-specific DNA binding. They may collaborate when bound together, but are assumed to be independent at sites where they bind alone. Hosokawa, Ungerbäck et al. show that PU.1 broadly shifts the genome-wide site choice of Runx1 DNA binding, enabling PU.1 to repress some target genes at a distance.
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- Möller, Christine, et al.
(författare)
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Bcl-2 and Bcl-XL are indispensable for the late phase of mast cell development from mouse embryonic stem cells
- 2007
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Ingår i: Experimental Hematology. - : Elsevier BV. - 0301-472X .- 1873-2399. ; 35:3, s. 385-393
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The aim of this study was to determine the importance of the prosurvival factors Bcl-2 and Bcl-XL for mast cell development and survival. Methods. bcl-x-/- and bcl-2-/- mouse embryonic stem cells were maintained in medium supplemented with either interleukin (IL)-3 or IL-3 in combination with stem cell factor (SCF) to favor mast cell development. The development of Bcl-2 family deficient embryonic stem cell-derived mast cells (ESMCs) was monitored and Bcl-2 family gene expression and cell numbers were analyzed. Results. Deficiency in either bcl-x or bcl-2 totally inhibited the development of ESMCs when IL-3 alone was used as a mast cell growth factor. Intriguingly, when IL-3 was used in combination with SCF, the ESMCs developed normally the first 2 weeks but thereafter the cell numbers dropped drastically. The remaining ESMCs express mouse mast cell protease 1, suggesting a mucosal-like phenotype. ESMCs lacking bcl-x or bcl-2 exhibited strong expression of Al, another prosurvival Bcl-2 family member. Conclusion. For the first time we provide direct evidence that both bcl-x and bcl-2 are indispensable for mast cell survival during the late phase of their development.
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