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- Title
Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation.
- Authors
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
- 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. Editor's summary: Dendritic cells (DCs) differentiate from bone marrow progenitors through a process guided by the cytokine Flt3 ligand (Flt3L). Using CRISPR-Cas9–based screening, Tiniakou et al. identified key regulators of murine Flt3L-driven DC differentiation including the arginine methyltransferase Carm1, mTOR-negative regulators TSC and GATOR1, and the transcriptional repressor Trim33. Trim33-deficient mice displayed a near-complete loss of multiple DC subsets with minimal impact on monocytes or granulocytes. During DC differentiation, Trim33 repressed expression of type I interferon and genes associated with other myeloid lineages. These findings identify Trim33 as a key transcriptional regulator of the Flt3L-driven pathway of DC differentiation. —Claire Olingy
- Subjects
DENDRITIC cells; CELL differentiation; TYPE I interferons; PROTEIN arginine methyltransferases; BONE marrow
- Publication
Science Immunology, 2024, Vol 9, Issue 94, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.adi1023