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NuRD complex recruitment to Thpok mediates CD4+ T cell lineage differentiation

ABSTRACT: NuRD complex recruitment to Thpok mediates CD4+ T cell lineage differentiation

PROVIDER: PRJNA821414 | ENA |

REPOSITORIES: ENA

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NuRD complex recruitment to Thpok mediates CD4+ T cell lineage differentiation

Project description: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 expression of most CD4+- and CD8+-lineage genes. Here, we identify the nucleosome remodeling and deacetylase (NuRD) complex as a novel Thpok cofactor. We locate three amino-acid residues within the Thpok BTB domain that are required for both NuRD binding and Thpok functions, and show that NuRD recruitment recapitulates the functions of the Thpok BTB domain. 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-zinc finger factors, which control the differentiation of most hematopoietic subsets.

2022-06-10 | GSE199739 | GEO

Gene expression in mature CD4 and CD8 from WT mice and mature CD4 from DBTBLZ or Mta2-DBTBLZ retrogenic mice

Project description:T cell precursors develop into cytotoxic CD8 and helper CD4+ T cells in thymus. Thpok, a BTB/POZ family transcription factor, enforces commitment to the CD4 lineage and suppresses cytotoxic gene expression. However, it is still not fully understood how Thpok directs CD4 T cell development. Here, using mass-spectrometry, we identify nucleosome remodeling and deacetylase (NuRD) complex as a novel Thpok cofactor. We demonstrate that the Thpok BTB domain is essential for NuRD recruitment. Reconstituting NuRD binding to a BTB-less version of Thpok (which cannot bind NuRD) restored CD4 T cell in vivo. RNA sequencing showed that CD4 T cells expressing the reconstituted protein express a transcriptome similar to that of CD4 T cells expressing Thpok. Thus, our results demonstrate that NuRD recruitment is both necessary and sufficient for the function of the Thpok BTB domain in CD4 T cell development.

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The NuRD complex is required for Thpok-mediated CD4+ T cell development

Project description:This data represent characterization of the interactome of murine Thpok. A version of Thpok (Thpok-Bio) subject to biotinylation in vivo by the BirA biotin ligase was used; to assess Thpok interactions in primary cells, Thpok-Bio was retrovirally expressed in in vitro activated CD4+ T cells from Thpokfl/fl Ox40-Cre+ mice carrying a Rosa26BirA allele. Expression of Ox40-Cre, initiated upon T cell activation, causes the deletion of endogenous Thpokfl alleles, so that transduced cells only express Thpok-Bio. Two Thpok deletion constructs (BKK and RFK) were also analyzed. Following streptavidin pulldown, proteins were separated by SDS-PAGE, the full lane cut into 9 slices, and in-gel digested. FIles are: 1384 - empty vector; 1385 - Thpok; 1386 - Thpok + Ethidium Bromide; 1387 - Thpok BKK; 1388 - Thpok RFK.

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NuRD complex recruitment to Thpok mediates CD4<sup>+</sup> T cell lineage differentiation.

Project description: Not available

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Gene expression in MHCII restricted mature thymocytes from Thpok-RKF- or Thpok-RKF+ Thpokfl/flRunx3fl/dYFPCd4-Cre+ mixed Bone marrow chimera.

Project description:Thpok-RKF which harbors a mutation in the BTB domain and disrupts the interaction between NuRD complex could not repress CD8 and CD8 lineage genes expression in Thpokfl/flRunx3fl/dYFPCd4-Cre+ from B2m-/- host. However, Thpok-RKF upregulates CD4 expression in these mice.

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Gene Expression in Effector T cells, wildtype of Thpok-deficient

Project description:The transcription factor Thpok is essential for CD4 T cell development in the thymus and remains expressed in post-thymic CD4 T cells. We post-thymically inactivated Thpok and compared microarray gene expression in Thpok-deficient CD4 T cells to that in their wildtype CD4 or CD8 counterparts We show that Thpok constrains the transcriptional circuitry to maintain CD4+-lineage integrity in naM-CM-/ve cells and to couple effector differentiation to environmental cues after antigenic stimulation. Redundantly with the related factor LRF, Thpok is continuously needed to prevent the trans-differentiation of mature CD4+ into -CD8+ T cells. We activated naM-CM-/ve CD4 T cells (either wild-type or Thpok-deficient) and CD8 T cells (wild-type) in vitro under Th1 conditions. Differentiated effectors were sorted 4 days after activation into CD4+CD8- and CD4-CD8+ (wild-type) and CD4+CD8- and CD4+CD8+ (Thpok-deficient) subsets. Total RNA was extracted from sorted subsets and processed for microarray analyses (Affymetrix Mouse Exon 1.0 ST array) at the NCI microarray facility, following the manufacturerM-bM-^@M-^Ys recommendation. Data is from 3 replicates (except wild-type CD4-CD8+ cells, for which two samples only were processed), generated from two distinct cell preparations.

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Project description:Genome-wide occupancy of the transcription factor Thpok in activated CD4+ T cells

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Thpok genome-wide occupancy in CD4+ T cells

Project description:Thpok genome-wide occupancy in CD4+ T cells

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Essential role of ThPOK autoregulatory loop in maintenance of mature CD4 T cell identity and function [RNA-seq]

Project description:The transcription factor ThPOK is critical for homeostasis and differentiation of mature T helper cells. Overall goal of this experiment is to show divergent gene expression profiles of ThPOK-dependent autoregulatory loop disrupted in CD4 T cells.

2021-04-05 | GSE168770 | GEO

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