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Intriniscally disordered domain of transcription factor TCF-1 is requried for T cell developmental fidelity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE213238 | GEO | 2023/07/06

REPOSITORIES: GEO

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Intrinsically disordered domain of transcription factor TCF-1 is required for T cell developmental fidelity.

Project description:In development, pioneer transcription factors access silent chromatin to reveal lineage-specific gene programs. The structured DNA-binding domains of pioneer factors have been well characterized, but whether and how intrinsically disordered regions affect chromatin and control cell fate is unclear. Here, we report that deletion of an intrinsically disordered region of the pioneer factor TCF-1 (termed L1) leads to an early developmental block in T cells. The few T cells that develop from progenitors expressing TCF-1 lacking L1 exhibit lineage infidelity distinct from the lineage diversion of TCF-1-deficient cells. Mechanistically, L1 is required for activation of T cell genes and repression of GATA2-driven genes, normally reserved to the mast cell and dendritic cell lineages. Underlying this lineage diversion, L1 mediates binding of TCF-1 to its earliest target genes, which are subject to repression as T cells develop. These data suggest that the intrinsically disordered N terminus of TCF-1 maintains T cell lineage fidelity.

| S-EPMC10919931 | biostudies-literature

Intrinsically disordered domain of transcription factor TCF-1 is required for T cell developmental fidelity

Project description:In development, pioneer transcription factors access silent chromatin to reveal lineage-specific gene programs. The structured DNA-binding domains of pioneer factors have been well characterized, but whether and how low-complexity intrinsically disordered regions (IDRs) affect chromatin and control cell fate is unclear. Here, we report deletion of an IDR of the pioneer factor TCF-1, termed “L1”, leads to an early developmental block in T cells. The few T cells that develop from progenitors expressing TCF-1 lacking L1 exhibit lineage infidelity distinct from the lineage diversion of TCF-1 deficient cells. Mechanistically, L1 is required for activation of T cell genes and de-repression of GATA2 driven genes, normally reserved to the mast cell and dendritic cell lineages. Underlying this lineage diversion, L1 mediates binding of TCF-1 to its earliest target genes which are subject to repression as T cells develop. These data suggest TCF-1’s intrinsically disordered N-terminus maintains T cell lineage fidelity.

2024-06-16 | PXD043586 | Pride

Intriniscally disordered domain of transcription factor TCF-1 is requried for T cell developmental fidelity [RNA-Seq]

Project description:The transcription factor TCF-1 has long been demonstrated to be essential for normal T cell development, with a critical role at the earliest stages of lineage specification downstream of Notch signaling in the thymus. Recent work has shown that TCF-1 targets and is essential for the opening of chromatin in T cells to orchestrate the gene regulatory cascade that occurs during development. However, besides the high mobility group DNA binding domain, no portion of the TCF-1 protein has been characterized to determine its role in hematopoiesis. In this study, we fully characterize all regions of TCF-1 and assess their importance in TCF-1-driven epigenetic and transcriptional regulation as well as in endowing developmental competency to the T cell lineage. Surprisingly, we identified an intrinsically disordered N-terminal region of TCF-1 termed “L1” that is necessary for efficient transition from early thymic progenitors to double-negative (DN)2 T cells. The few T cells that develop from progenitor cells expressing mutant TCF-1 lacking the L1 region exhibit lineage infidelity that was distinct and unique from the lineage diversion of TCF-1-deficient cells. Transcriptional and epigenetic profiling indicated that the L1 region was required for efficient target gene transactivation which correlated with the de-repression of a set of Gata2-driven genes normally restricted to the mast cell and dendritic cell lineages. DL1 mutant DN2 cells showed aberrant opening of previously silent chromatin at mast cell genes and Gata2-bound enhancers. These data support an essential role for TCF-1’s intrinsically disordered N-terminus in maintaining fidelity to the T cell lineage through carefully balanced activation of partner transcription factors that are required to repress alternative lineages.

2023-07-06 | GSE213236 | GEO