Essential function for SWI-SNF chromatin-remodeling complexes in the promoter-directed assembly of Tcrb genes

Osipovich, Oleg; Cobb, Robin Milley; Oestreich, Kenneth J; Pierce, Steven; Ferrier, Pierre; Oltz, Eugene M.

doi:10.1038/ni1481

Cited by 61 publications

(62 citation statements)

References 51 publications

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“…A highly flexible structure is consistent with reported extensive remodeling of chromatin at this genomic region during rearrangement, by protein factors such as switch/sucrose nonfermentable protein complex (SWI/SNF) (27) and high-mobility group proteins (HMG) (28). The latter protein had been shown to decrease greatly the persistence length of naked DNA, from ∼50 nm to only ∼5 nm (29).…”

Section: Mechanical Model Of Chromatin Explains Observed Biases In Jβ-dβsupporting

confidence: 58%

“…The ability of chromatin conformation to explain rearrangement frequencies at these other receptor loci will depend on the magnitude of the contributions from other factors (1,23,24,27,28,(34)(35)(36)(37) that influence the rearrangement process. In particular, the demonstrated effect of chromatin conformation on gene segment use is potentially further modulated by cis-acting elements such as RSSs (1,23,24,34), coding ends of genes (35), Vβ/Dβ promoters (34), and other molecular factors that regulate the accessibility of individual genes to enzymes involved in VDJ rearrangement (27,28,36,37). Additionally, gene segment use may be further modulated by thymic selection, homeostatic T-cell expansion in peripheral lymphoid organs, and clonal expansion during specific immune responses (38).…”

Section: Discussionmentioning

confidence: 99%

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Chromatin conformation governs T-cell receptor Jβ gene segment usage

Ndifon

Gal

Shifrut

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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T cells play fundamental roles in adaptive immunity, relying on a diverse repertoire of T-cell receptor (TCR) α and β chains. Diversity of the TCR β chain is generated in part by a random yet intrinsically biased combinatorial rearrangement of variable (Vβ), diversity (Dβ), and joining (Jβ) gene segments. The mechanisms that determine biases in gene segment use remain unclear. Here we show, using a high-throughput TCR sequencing approach, that a physical model of chromatin conformation at the DJβ genomic locus explains more than 80% of the biases in Jβ use that we measured in murine T cells. This model also predicts correctly how differences in intersegment genomic distances between humans and mice translate into differences in Jβ bias between TCR repertoires of these two species. As a consequence of these structural and other biases, TCR sequences are produced with different a priori frequencies, thus affecting their probability of becoming public TCRs that are shared among individuals. Surprisingly, we find that many more TCR sequences are shared among all five mice we studied than among only subgroups of three or four mice. We derive a necessary mathematical condition explaining this finding, which indicates that the TCR repertoire contains a core set of receptor sequences that are highly abundant among individuals, if their a priori probability of being produced by the recombination process is higher than a defined threshold. Our results provide evidence for an expanded role of chromatin conformation in VDJ rearrangement, from control of gene accessibility to precise determination of gene segment use.lymphocyte receptor repertoires | public T-cell clones | VDJ recombination | epigenetics | next generation sequencing

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Section: Mechanical Model Of Chromatin Explains Observed Biases In Jβ-dβsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Chromatin conformation governs T-cell receptor Jβ gene segment usage

Ndifon

Gal

Shifrut

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…BRG1 stimulates in vitro recombination of chromatin and is also bound to regions in the T-cell receptor (TCR) and immunoglobulin loci that take part in recombination events (Golding et al, 1999;Kwon et al, 2000;Spicuglia et al, 2002;Morshead et al, 2003;Patenge et al, 2004). More recent studies have shown SWI/SNF to be fundamental to the promoter-directed assembly of TCR-b (TCRB) genes (Osipovich et al, 2007); SWI/ SNF is recruited to promoters and then facilitates recombination by exposing segments of genomic DNA to V(D)J recombinase. The fact that loss of this chromatin-remodeling complex in thymocytes inactivates recombinase targets at the endogenous TCRB locus (Osipovich et al, 2007) provides further evidence for the role of SWI/SNF in recombination.…”

Section: Brm and Brg1 Control The Expression Of Genes That Are Involvmentioning

confidence: 99%

“…More recent studies have shown SWI/SNF to be fundamental to the promoter-directed assembly of TCR-b (TCRB) genes (Osipovich et al, 2007); SWI/ SNF is recruited to promoters and then facilitates recombination by exposing segments of genomic DNA to V(D)J recombinase. The fact that loss of this chromatin-remodeling complex in thymocytes inactivates recombinase targets at the endogenous TCRB locus (Osipovich et al, 2007) provides further evidence for the role of SWI/SNF in recombination.…”

Section: Brm and Brg1 Control The Expression Of Genes That Are Involvmentioning

confidence: 99%

The SWI/SNF complex and cancer

2009

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The mammalian SWI/SNF complexes mediate ATPdependent chromatin remodeling processes that are critical for differentiation and proliferation. Not surprisingly, loss of SWI/SNF function has been associated with malignant transformation, and a substantial body of evidence indicates that several components of the SWI/SNF complexes function as tumor suppressors. This review summarizes the evidence that underlies this conclusion, with particular emphasis upon the two catalytic subunits of the SWI/SNF complexes, BRM, the mammalian ortholog of SWI2/SNF2 in yeast and brahma in Drosophila, and Brahma-related gene-1 (BRG1).

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“…SWI/SNF CRCs are important for controlling differentiation and proliferation in many cell types. In lymphocytes, CRCs have been implicated in activating transcription and antigen receptor rearrangements (8)(9)(10).…”

Section: T He Development Of B Cells From Progenitor Cells In the Bonementioning

confidence: 99%

Opposing effects of SWI/SNF and Mi-2/NuRD chromatin remodeling complexes on epigenetic reprogramming by EBF and Pax5

Gao

Lukin

Ramírez

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

131

132

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Transcriptionally silent genes are maintained in inaccessible chromatin. Accessibility of these genes requires their modification by chromatin remodeling complexes (CRCs), which are recruited to promoters by sequence-specific DNA-binding proteins. Early B-cell factor (EBF), which is crucial for B-cell lineage specification, reprograms mb-1 (Ig-␣) promoters by increasing chromatin accessibility and initiating the loss of DNA methylation. In turn, this facilitates promoter activation by Pax5. Here, we investigated the roles of ATP-dependent CRCs in these mechanisms. Fusion of EBF and Pax5 with the ligand-binding domain of ER␣ allowed for 4-hydroxytamoxifen-dependent, synergistic activation of mb-1 transcription in plasmacytoma cells. Knockdown of the SWI/SNF ATPases Brg1 and Brm inhibited transcriptional activation by EBF:ER and Pax5:ER. In contrast, knock-down of the Mi-2/NuRD complex subunit Mi-2␤ greatly enhanced chromatin accessibility and mb-1 transcription in response to the activators. The reduction of Mi-2␤ also propagated DNA demethylation in response to EBF:ER and Pax5:ER, resulting in fully unmethylated mb-1 promoters. In EBF-or EBF/Pax5-deficient fetal liver cells, both EBF and Pax5 were required for efficient demethylation of mb-1 promoters. Together, our data suggest that Mi-2/NuRD is important for the maintenance of hypermethylated chromatin in B cells. We conclude that SWI/SNF and Mi-2/NuRD function in opposition to enable or limit the reprogramming of genes by EBF and Pax5 during B-cell development.DNA methylation ͉ mb-1 promoter ͉ Cd19 promoter ͉ chromatin accessibility T he development of B cells from progenitor cells in the bone marrow is controlled by a network of transcriptional regulators (reviewed in 1). Early B-cell Factor (EBF; also known as EBF1/O/E-1/COE1) plays an integral role in this network and has been implicated as a major determinant of the B-cell fate (2, 3). In the absence of EBF, B-cell development is arrested at an early progenitor stage (3, 4). EBF is essential for the rearrangement and expression of Ig (Ig) genes in B cells and is required for expression of the B-cell commitment factor Pax5. EBF and Pax5 synergistically activate transcription of B cell-specific genes including mb-1 (Cd79a), which encodes the Ig-␣ subunit of the pre-B and B-cell receptors (5). We have proposed that EBF functions as a 'pioneer' factor by controlling the epigenetic states of its target genes (6). In response to EBF, the accessibility of mb-1 promoter chromatin is increased, while DNA methylation of the promoter is decreased.Specific biochemical interactions necessary for the pioneer functions of EBF have not been identified. However, transitions between active and inactive states of chromatin can be mediated by the recruitment of chromatin-remodeling complexes (CRCs) by transcription factors (7). CRCs serve as 'molecular motors' that mediate changes in the relative positions of nucleosomes. In this regard, CRCs of the mammalian SWI/SNF (related to yeast switch/sucrose non-Fermenter) subfamily ...

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Essential function for SWI-SNF chromatin-remodeling complexes in the promoter-directed assembly of Tcrb genes

Cited by 61 publications

References 51 publications

Chromatin conformation governs T-cell receptor Jβ gene segment usage

Chromatin conformation governs T-cell receptor Jβ gene segment usage

The SWI/SNF complex and cancer

Opposing effects of SWI/SNF and Mi-2/NuRD chromatin remodeling complexes on epigenetic reprogramming by EBF and Pax5

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