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- Title
NuRD complex recruitment to Thpok mediates CD4<sup>+</sup> T cell lineage differentiation.
- Authors
Gao, Yayi; Zamisch, Monica; Vacchio, Melanie; Chopp, Laura; Ciucci, Thomas; Paine, Elliott L.; Lyons, Gaelyn C.; Nie, Jia; Xiao, Qi; Zvezdova, Ekaterina; Love, Paul E.; Vinson, Charles R.; Jenkins, Lisa M.; Bosselut, Rémy
- Abstract
Although BTB–zinc finger (BTB-ZF) transcription factors control the differentiation of multiple hematopoietic and immune lineages, how they function is poorly understood. The BTB-ZF factor Thpok controls intrathymic CD4+ T cell development and the expression of most CD4+ and CD8+ lineage genes. Here, we identify the nucleosome remodeling and deacetylase (NuRD) complex as a critical Thpok cofactor. Using mass spectrometry and coimmunoprecipitation in primary T cells, we show that Thpok binds NuRD components independently of DNA association. We locate three amino acid residues within the Thpok BTB domain that are required for both NuRD binding and Thpok functions. Conversely, a chimeric protein merging the NuRD component Mta2 to a BTB-less version of Thpok supports CD4+ T cell development, indicating that NuRD recruitment recapitulates the functions of the Thpok BTB domain. We found that NuRD mediates Thpok repression of CD8+ lineage genes, including the transcription factor Runx3, but is dispensable for Cd4 expression. We show that these functions cannot be performed by the BTB domain of the Thpok-related factor Bcl6, which fails to bind NuRD. Thus, cofactor binding critically contributes to the functional specificity of BTB-ZF factors, which control the differentiation of most hematopoietic subsets. A NuRDy partner for Thpok: The BTB-ZF transcription factor Thpok is essential for development of CD4+ T cells. However, the molecular mechanisms through which Thpok regulates transcription during CD4+ lineage commitment are not well defined. Gao et al. analyzed proteins interacting with Thpok in primary CD4+ T cells and identified components of the nucleosome remodeling and deacetylase (NuRD) complex. Using a series of genetically modified Thpok variants in vivo, they identified three amino acids in the BTB domain of Thpok that are required for interactions with NuRD and for subsequent repression of CD8+ lineage genes including Runx3. These findings identify the NuRD complex as a cofactor required for Thpok-mediated repression of CD8+ lineage genes, increasing our understanding of CD4+ lineage commitment and BTB-ZF transcription factor function.
- Publication
Science Immunology, 2022, Vol 7, Issue 72, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.abn5917