Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation

Tiniakou, Ioanna; Hsu, Pei-Feng; Lopez-Zepeda, Lorena S.; Garipler, Görkem; Esteva, Eduardo; Adams, Nicholas M.; Jang, Geunhyo; Soni, Chetna; Lau, Colleen M.; Liu, Fan; Khodadadi-Jamayran, Alireza; Rodrick, Tori C.; Jones, Drew; Tsirigos, Aristotelis; Ohler, Uwe; Bedford, Mark T.; Nimer, Stephen D.; Kaartinen, Vesa; Mazzoni, Esteban O.; Reizis, Boris

doi:10.1126/sciimmunol.adi1023

Cited by 2 publications

(1 citation statement)

References 95 publications

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“…While the role of TIF1γ in the immune system has been previously explored in HSCs, NKT cells, macrophages, Th17 cells, and more recently DCs (1,16,(42)(43)(44); the relevance of TIF1γ for Treg function and stability has been largely ignored. Previous attempts to demonstrate a role for TIF1γ in T cell development using a CD4-Cre TIF1γ cKO mice, showed no effect on T cell differentiation in the thymus mostly focusing on CD4 and CD8 SP development, while NKT cell development was partially impaired (42).…”

Section: Discussionmentioning

confidence: 99%

TIF1γ regulates stability of T regulatory cells during inflammation

Contreras-Castillo,

Zambrano-Romero,

Pérez-Vázquez

et al. 2024

Preprint

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T regulatory cells are a suppressor population critical to control inflammation and maintain tissue homeostasis. The TGF-β pathway is a fundamental signal for T regulatory cell differentiation, yet the molecular determinants of how TGF-β signals regulate all these processes are not completely understood. TIF1γ was demonstrated to promote a noncanonical TGF-β/Smad pathway in HSC, however the role of TIF1γ in Treg function has been largely ignored. Here we showed that TIF1γ deficient Tregs lose stability and acquire an effector phenotype in the presence of an inflammatory stimuli or upon activation. TIF1γ deficient T regs gain a Th1-like Treg phenotype or become pro-inflammatory exTregs, by losing Foxp3 expression and acquiring IFNγ expression in an autoimmune model. Loss of TIF1γ in Tregs was cell-intrinsic and was also accompanied by increased proliferation and enhanced glycolytic capacity upon activation. Additionally, we demonstrated that in the absence of TIF1γ, there was an increased methylation status in the CNS2 enhancer region of the Foxp3 locus, further suggesting increased susceptibility for loss of Foxp3 expression. Mechanistically, TGF-β was in part responsible to inhibit the Th1-like bias a Treg has in the absence of TIF1γ, however, the proliferative phenotype observed in these cells was mostly independent of TGF-β signaling. Finally, we identified the beta-catenin pathway as the molecular mechanism driving both TIF1γ-dependent Treg stability and proliferation upon inflammation. Altogether, our data demonstrated that TIF1γ is required for the maintenance of a suppressor phenotype and stability of Treg lymphocytes during inflammatory conditions in vivo and represents a new modulatory pathway to manipulate Treg cells for therapeutic purposes.

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Section: Discussionmentioning

confidence: 99%

TIF1γ regulates stability of T regulatory cells during inflammation

Contreras-Castillo,

Zambrano-Romero,

Pérez-Vázquez

et al. 2024

Preprint

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Cohesin-mediated chromatin remodeling controls the differentiation and function of conventional dendritic cells

Adams,

Galitsyna,

Tiniakou

et al. 2024

Preprint

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The cohesin protein complex extrudes chromatin loops, stopping at CTCF-bound sites, to organize chromosomes into topologically associated domains, yet the biological implications of this process are poorly understood. We show that cohesin is required for the post-mitotic differentiation and function of antigen-presenting dendritic cells (DCs), particularly for antigen cross-presentation and IL-12 secretion by type 1 conventional DCs (cDC1s) in vivo. The chromatin organization of DCs was shaped by cohesin and the DC-specifying transcription factor IRF8, which controlled chromatin looping and chromosome compartmentalization, respectively. Notably, optimal expression of IRF8 itself required CTCF/cohesin-binding sites demarcating the Irf8 gene. During DC activation, cohesin was required for the induction of a subset of genes with distal enhancers. Accordingly, the deletion of CTCF sites flanking the Il12b gene reduced IL-12 production by cDC1s. Our data reveal an essential role of cohesin-mediated chromatin regulation in cell differentiation and function in vivo, and its bi-directional crosstalk with lineage-specifying transcription factors.

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Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation

Cited by 2 publications

References 95 publications

TIF1γ regulates stability of T regulatory cells during inflammation

TIF1γ regulates stability of T regulatory cells during inflammation

Cohesin-mediated chromatin remodeling controls the differentiation and function of conventional dendritic cells

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