The SWI/SNF-like BAF Complex Is Essential for Early B Cell Development

Jeon

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

et al. 2015

Self Cite

Germinal center (GC) reaction is crucial in adaptive immune responses. The formation of GC is coordinated by the expression of specific genes including Blimp-1 and Bcl-6. Although gene expression is critically influenced by the status of chromatin structure, little is known about the role of chromatin remodeling factors for regulation of GC formation. Here, we show that the SWI/SNF chromatin remodeling complex is required for GC reactions. Mice lacking Srg3/mBaf155, a core component of the SWI/SNF complex, showed impaired differentiation of GC B and follicular helper T cells in response to T cell-dependent antigen challenge. The SWI/SNF complex regulates chromatin structure at the Blimp-1 locus and represses its expression by interacting cooperatively with Bcl-6 and corepressors. The defect in GC reactions in mice lacking Srg3 was due to the derepression of Blimp-1 as supported by genetic studies with Blimp-1–ablated mice. Hence, our study identifies the SWI/SNF complex as a key mediator in GC reactions by modulating Bcl-6–dependent Blimp-1 repression.

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The SWI/SNF chromatin remodeling complex regulates germinal center formation by repressing Blimp-1 expression

Jeon

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

et al. 2015

Self Cite

“…21 To further investigate how the loss of both BAF155 and BAF170 affects forebrain development, we generated forebrain-specific BAF155 and BAF170 dcKO mice by crossing mice floxed for BAF155 22 and…”

Section: Resultsmentioning

confidence: 99%

Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development

et al. 2016

The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development.

“…The mAbs used for FACS were described previously [43] and anti-CD34 (RAM34), anti-Flt3 (12B6), anti-TNF (MP6-XT22), anti-IFN-γ (XMG1.2), anti-IL-17A (17B7), anti-IL-6 (MP5-20F3), and anti-GM-CSF (MP1-22E9) were purchased from BD Biosciences or eBiosciences.…”

Section: Flow Cytometry and Cell Sortingmentioning

confidence: 99%

Foxp3⁺ regulatory T cells ensure B lymphopoiesis by inhibiting the granulopoietic activity of effector T cells in mouse bone marrow

et al. 2014

Self Cite

Foxp3 + Treg cells are crucial for maintaining T-cell homeostasis, but their role in B-cell homeostasis remains unclear. Here, we found that Foxp3 mutant scurfy mice had fewer B-lineage cells and progenitors, including common lymphoid progenitors and lymphoidprimed multipotent progenitors, but higher myeloid-lineage cell numbers in BM compared with WT littermates. Homeostasis within the HSC compartment was also compromised with apparent expansion of long-and short-term HSCs. This abnormality was due to the lack of Treg cells, but not to the Treg-cell extrinsic functions of Foxp3 or cellautonomous defects. Among cytokines enriched in the BM of scurfy mice, IFN-γ affected only B lymphopoiesis, but GM-CSF, TNF, and IL-6 collectively promoted granulopoiesis at the expense of B lymphopoiesis. Neutralization of these three cytokines reversed the hematopoietic defects on early B-cell progenitors in scurfy mice. Treg cells ensured B lymphopoiesis by reducing the production of these cytokines by effector T cells, but not by directly affecting B lymphopoiesis. These results suggest that Treg cells occupy an important niche in the BM to protect B-lineage progenitor cells from excessive exposure to a lymphopoiesis-regulating milieu.Keywords: B lymphopoiesis r Foxp3 r Granulopoietins r Hematopoiesis r Regulatory T cells Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction CD4 + Foxp3 + Treg cells are essential for maintaining immune homeostasis, as evidenced by the severe autoimmune lymphoproliferative disease observed in Treg-cell-deficient mice and humans [1,2]. Treg cells were initially identified in the secondary lymphoid tissues where they suppress the initial priming and Correspondence: Prof. Jeehee Youn e-mail: jhyoun@hanyang.ac.kr effector differentiation of autoreactive T cells [3]. They function by directly suppressing T cells and/or interacting with DCs to limit their ability to prime T cells effectively [4,5]. In addition to their constitutive presence in secondary lymphoid tissues, Treg cells have been found in several nonlymphoid sites, such as mucosal tissue, skin, liver, and lung, during inflammation as well as in steady-state conditions [6][7][8][9][10]. These Treg cells appear to regulate * These authors contributed equally to this work. * * These senior authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 168Sunghoon Kim et al. Eur. J. Immunol. 2015. 45: 167-179 tissue-tropic autoimmunity and inflammation, and alter pathogen clearance during peripheral infection. A diverse array of adhesion molecules and chemokine receptors that are expressed on Treg cells seem to license them to migrate to peripheral tissues. A fraction of Treg cells have been shown to express the BM homing receptor CXCR4 [11], suggesting the existence of a niche for Treg cells in the BM. Indeed, there are studies showing that healthy human BM contains a substantial number of Treg cells that traffic via CXC...