Chromatin remodeling complex NURF regulates thymocyte maturation

Abstract

The maturation of T cells requires signaling from both cytokine and T-cell receptors to gene targets in chromatin, but how chromatin architecture influences this process is largely unknown. Here we show that thymocyte maturation post-positive selection is dependent on the nucleosome remodeling factor (NURF). Depletion of Bptf (bromodomain PHD finger transcription factor), the largest NURF subunit, in conditional mouse mutants results in developmental arrest beyond the CD4 + CD8 int stage without affecting cellular proliferation, cellular apoptosis, or coreceptor gene expression. In the Bptf mutant, specific subsets of genes important for thymocyte development show aberrant expression. We also observed defects in DNase I-hypersensitive chromatin structures at Egr1, a prototypical Bptf-dependent gene that is required for efficient thymocyte development. Moreover, chromatin binding of the sequence-specific factor Srf (serum response factor) to Egr1 regulatory sites is dependent on Bptf function. Physical interactions between NURF and Srf suggest a model in which Srf recruits NURF to facilitate transcription factor binding at Bptf-dependent genes. These findings provide evidence for causal connections between NURF, transcription factor occupancy, and gene regulation during thymocyte development.

Functional Interactions between NURF and Ctcf Regulate Gene Expression

“…Interestingly, Bptf-dependent NFRs were overrepresented at the major histocompatibility complex (MHC) genes and HOX gene clusters, each of which contains many Bptf-dependent genes ( Fig. 2F; also, see Table S1 in the supplemental material) (17,18). These results suggest that Bptf has significance for maintaining unique chromatin structures at these regions, which are important for gene expression.…”

“…1B). Bptf-dependent changes in gene expression were subsequently determined genome-wide by microarray analysis in MEFs, as described previously for ESCs and DP thymocytes (see Tables S1 and S2 in the supplemental material) (17,18). While the genes identified by this approach require Bptf for normal expression, the changes in gene expression could be the result of either direct or indirect effects of Bptf KO.…”

ATP-dependent chromatin remodeling during mammalian development

“…The SNF2L-containing NURF complex has essential roles in thymocyte development and erythropoiesis (Landry et al, 2011;Stopka and Skoultchi, 2003). During thymocyte development, the NURF subunit BPTF is essential for the differentiation of CD4 or CD8 single-positive cells to mature T cells and functions by regulating the expression of several thymocyte maturation genes in a TCR-signaling dependent manner.…”

“…NURF is required during post-implantation embryonic development and ESC differentiation (Landry et al, 2008) and for thymocyte maturation (Landry et al, 2011) CERF SNF2L, CECR2 SNF2L is required during neurogenesis (Yip et al, 2012) and oogenesis (Pépin et al, 2013) CERF is involved in neurulation (Banting et al, 2005) *Current mouse gene symbols are listed only where they differ from protein nomenclature.…”

“…During thymocyte development, the NURF subunit BPTF is essential for the differentiation of CD4 or CD8 single-positive cells to mature T cells and functions by regulating the expression of several thymocyte maturation genes in a TCR-signaling dependent manner. BPTF regulates DNaseI hypersensitivity and interacts with the transcription factor SRF to regulate NURF recruitment at Egr1, a thymocyte maturation-specific gene (Landry et al, 2011). SNF2H, by contrast, is required for the proliferation of early stage hematopoietic progenitor cells during erythropoiesis (Stopka and Skoultchi, 2003).…”