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

Item Type:Article
Title:Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation
Creators Name:Tiniakou, I. and Hsu, P.F. and Lopez-Zepeda, L.S. and Garipler, G. and Esteva, E. and Adams, N.M. and Jang, G. and Soni, C. and Lau, C.M. and Liu, F. and Khodadadi-Jamayran, A. and Rodrick, T.C. and Jones, D. and Tsirigos, A. and Ohler, U. and Bedford, M.T. and Nimer, S.D. and Kaartinen, V. and Mazzoni, E.O. and Reizis, B.
Abstract:The development of dendritic cells (DCs), including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs), is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected Flt3L-driven DC differentiation using CRISPR-Cas9-based screening. Genome-wide screening identified multiple regulators of DC differentiation including subunits of TSC and GATOR1 complexes, which restricted progenitor growth but enabled DC differentiation by inhibiting mTOR signaling. An orthogonal screen identified the transcriptional repressor Trim33 (TIF-1γ) as a regulator of DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes or granulocytes. In particular, deletion of Trim33 caused rapid loss of DC progenitors, pDCs, and the cross-presenting cDC1 subset. Trim33-deficient Flt3(+) progenitors up-regulated pro-inflammatory and macrophage-specific genes but failed to induce the DC differentiation program. Collectively, these data elucidate mechanisms that control Flt3L-driven differentiation of the entire DC lineage and identify Trim33 as its essential regulator.
Keywords:Cell Differentiation, Chorea, Cytokines, Dendritic Cells
Source:Science Immunology
Publisher:American Association for the Advancement of Science
Page Range:eadi1023
Date:12 April 2024
Official Publication:https://doi.org/10.1126/sciimmunol.adi1023
PubMed:View item in PubMed

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