Project Details
Description
Project Summary
The transcription factor STAT5 plays key roles in governing the development of multiple CD4+ T cell lineages,
including regulatory T cells (Tregs) and T follicular helper cells (TFH). STAT5 does this by both initiating and
inhibiting gene transcription. However, the molecular mechanisms that determine whether STAT5 binding
leads to gene transcription or gene silencing remain largely unknown. STAT5 has been shown to interact with
the co-activators EP300 and CREBBP and this has been suggested to modulate STAT5 function; however, co-
repressors that functionally modulate STAT5 function remain essentially undefined. Equally unclear is whether
STAT5:co-repressor complexes are preferentially targeted to STAT5-repressed genes, and if so, what the
mechanism is that accounts for this differential targeting. Thus, key gaps in our current knowledge of
STAT5 function in T cells include: (i) identification of biologically relevant STAT5:co-repressor
complexes that affect T cell development, (ii) information about how STAT5:co-repressor complexes
affect gene expression in T cells, and (iii) molecular insights into how STAT5 differentially targets co-
repressor complexes to STAT5-repressed genes. Our preliminary data strongly supports a key role for the
co-repressors NCOR1 and NCOR2 in regulating STAT5-dependent T cell differentiation. Deletion of either
Ncor1 or Ncor2 had relatively mild effects on T cell development. In contrast, deletion of both Ncor1 and Ncor2
had dramatic impacts on T cell differentiation in the thymus. These impacts included a striking block in the
development of FOXP3+ regulatory T cells in the thymus, and a clear increase in T follicular helper cells in
Peyers patches. Thus, loss of NCOR1/2 in T cells parallels several of the phenotypes observed in STAT5
knockout mice. Our overarching hypothesis is that STAT5 interactions with the co-repressors NCOR1
and NCOR2 play a critical role in T cell development. We further propose that STAT5/NCOR complexes
are targeted to a unique subset of STAT5-repressed genes via sequence-specific DNA binding sites or
interactions with other transcription factors that also help recruit NCOR co-repressor complexes.
Successful completion of these aims will provide insights into the mechanism by which STAT5 alters gene
transcription and chromatin structure to promote T cell differentiation. It will also provide fundamental insights
into the mechanisms by which transcription factors can selectively repress transcription of specific genes
without blocking transcription of other genes induced by that same transcription factor.
Status | Finished |
---|---|
Effective start/end date | 5/10/19 → 4/30/24 |
Funding
- National Institute of Allergy and Infectious Diseases: $484,777.00
- National Institute of Allergy and Infectious Diseases: $484,777.00
- National Institute of Allergy and Infectious Diseases: $484,777.00
- National Institute of Allergy and Infectious Diseases: $484,777.00
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