biostudies-literatureGao YIntramural NIH HHSeabn5917https://www.ebi.ac.uk/biostudies/studies/S-EPMC9484726biostudies-literatureUnknown7(72)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 suScience immunologyNuRD complex recruitment to Thpok mediates CD4<sup>+</sup> T cell lineage differentiation.PMC9484726Z99 CA999999Vacchio MNie JVinson CRCiucci TLyons GCJenkins LMXiao QZvezdova ELove PEBosselut RGao YZamisch MPaine ELChopp LfalseNuRD complex recruitment to Thpok mediates CD4<sup>+</sup> T cell lineage differentiation.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 su2022-01-01T00:00:00Z2022 Jun2026-05-28T00:38:58.764Z2025-04-04T23:36:37.34ZS-EPMC94847263568769810.1126/sciimmunol.abn5917