Chromatin remodeling by the NuRD complex regulates development of follicular helper and regulatory T cells

Shen, Erxia; Wang, Qin; Rabe, Hardis; Liu, Wenquan; Cantor, Harvey; Leavenworth, Jianmei W.

doi:10.1073/pnas.1805239115

Cited by 37 publications

(20 citation statements)

References 24 publications

(47 reference statements)

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“…Hence, our findings imply an important involvement of NuRD-associated CHD3 and CHD4 in RNase1 repression in inflamed human ECs. These findings are supported by the essential roles of NuRD in context of inflammation, e.g., in regulation of T- and B-cell development or macrophage immune responses ( Fujita et al, 2004 ; Shimizu-Hirota et al, 2012 ; Shen et al, 2018 ). The great impact of NuRD co-repressor complex in RNase1 regulation is further confirmed by recruitment of CHD4 to the RNASE1 promoter Region A upon 10 min TNF-α treatment.…”

Section: Discussionmentioning

confidence: 54%

p38 and Casein Kinase 2 Mediate Ribonuclease 1 Repression in Inflamed Human Endothelial Cells via Promoter Remodeling Through Nucleosome Remodeling and Deacetylase Complex

Bedenbender

Beinborn

Vollmeister

et al. 2020

Front. Cell Dev. Biol.

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Vascular pathologies, such as thrombosis or atherosclerosis, are leading causes of death worldwide and are strongly associated with the dysfunction of vascular endothelial cells. In this context, the extracellular endonuclease Ribonuclease 1 (RNase1) acts as an essential protective factor in regulation and maintenance of vascular homeostasis. However, long-term inflammation causes strong repression of RNase1 expression, thereby promoting endothelial cell dysfunction. This inflammation-mediated downregulation of RNase1 in human endothelial cells is facilitated via histone deacetylase (HDAC) 2, although the underlying molecular mechanisms are still unknown. Here, we report that inhibition of c-Jun N-terminal kinase by small chemical compounds in primary human endothelial cells decreased physiological RNase1 mRNA abundance, while p38 kinase inhibition restored repressed RNase1 expression upon proinflammatory stimulation with tumor necrosis factor alpha (TNF-α) and poly I:C. Moreover, blocking of the p38 kinase- and HDAC2-associated kinase casein kinase 2 (CK2) by inhibitor as well as small interfering RNA (siRNA)-knockdown restored RNase1 expression upon inflammation of human endothelial cells. Further downstream, siRNA-knockdown of chromodomain helicase DNA binding protein (CHD) 3 and 4 of the nucleosome remodeling and deacetylase (NuRD) complex restored RNase1 repression in TNF-α treated endothelial cells implicating its role in the HDAC2-containing repressor complex involved in RNase1 repression. Finally, chromatin immunoprecipitation in primary human endothelial cells confirmed recruitment of the CHD4-containing NuRD complex and subsequent promoter remodeling via histone deacetylation at the RNASE1 promoter in a p38-dependent manner upon human endothelial cell inflammation. Altogether, our results suggest that endothelial RNase1 repression in chronic vascular inflammation is regulated by a p38 kinase-, CK2-, and NuRD complex-dependent pathway resulting in complex recruitment to the RNASE1 promoter and subsequent promoter remodeling.

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Section: Discussionmentioning

confidence: 54%

p38 and Casein Kinase 2 Mediate Ribonuclease 1 Repression in Inflamed Human Endothelial Cells via Promoter Remodeling Through Nucleosome Remodeling and Deacetylase Complex

Bedenbender

Beinborn

Vollmeister

et al. 2020

Front. Cell Dev. Biol.

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“…Foxp3 and Bcl-6 are the master transcriptional factors for Tfr cell differentiation. Defects in the Bcl-6–nucleosome remodeling and deacetylase complex impair Tfr cell development [ 51 ]. Foxp3, along with the chromatin-modifying enzyme enhancer of zeste homolog 2, possesses the capacity to convert Tfh cells into functional suppressive Tfr-like cells [ 27 ].…”

Section: Modulators Of Tfr Cell Differentiationmentioning

confidence: 99%

Differentiation, functions, and roles of T follicular regulatory cells in autoimmune diseases

Nakayamada

Tanaka

2021

Inflamm Regener

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T follicular helper cells participate in stimulating germinal center (GC) formation and supporting B cell differentiation and autoantibody production. However, T follicular regulatory (Tfr) cells suppress B cell activation. Since changes in the number and functions of Tfr cells lead to dysregulated GC reaction and autoantibody response, targeting Tfr cells may benefit the treatment of autoimmune diseases. Differentiation of Tfr cells is a multistage and multifactorial process with various positive and negative regulators. Therefore, understanding the signals regulating Tfr cell generation is crucial for the development of targeted therapies. In this review, we discuss recent studies that have elucidated the roles of Tfr cells in autoimmune diseases and investigated the modulators of Tfr cell differentiation. Additionally, potential immunotherapies targeting Tfr cells are highlighted.

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“…5,53 Bcl6dependent control of follicular T cells is mediated by a complex formed between Bcl6 and the Mi2β-nucleosome-remodeling deacetylase complex (Mi-2β-NuRD), with intracellular isoform of osteopontin (OPNi) acting as a scaffold between the two. 53 OPNi may also shield Bcl6 from ubiquination. 47 Blimp-1 has been reported to maintain Tfr cell lineage stability by repressing the IL-23R-STAT3 axis and activating the CD25-STAT5 pathway.…”

Section: Molecules and Signals Modulating Tfr Cell Development And Differentiationmentioning

confidence: 99%

Follicular regulatory T cell biology and its role in immune-mediated diseases

Wang

Huang

2021

Journal of Leukocyte Biology

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Follicular regulatory T (Tfr) cells are recently found to be a special subgroup of regulatory T (Treg) cells. Tfr cells play an important role in regulating the germinal center (GC) response, especially modulating follicular helper T (Tfh) cells and GC-B cells, thereby affecting the production of antibodies. Tfr cells are involved in the generation and development of many immune-related and inflammatory diseases. This article summarizes the advances in several aspects of Tfr cell biology, with special focus on definition and phenotype, development and differentiation, regulatory factors, functions, and interactions with T/B cells and molecules involved in performance and regulation of Tfr function. Finally, we highlight the current understanding of Tfr cells involvement in autoimmunity and alloreactivity, and describe some drugs targeting Tfr cells. These latest studies have answered some basic questions in Tfr cell biology and explored the roles of Tfr cells in immune-mediated diseases.

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Chromatin remodeling by the NuRD complex regulates development of follicular helper and regulatory T cells

Cited by 37 publications

References 24 publications

p38 and Casein Kinase 2 Mediate Ribonuclease 1 Repression in Inflamed Human Endothelial Cells via Promoter Remodeling Through Nucleosome Remodeling and Deacetylase Complex

p38 and Casein Kinase 2 Mediate Ribonuclease 1 Repression in Inflamed Human Endothelial Cells via Promoter Remodeling Through Nucleosome Remodeling and Deacetylase Complex

Differentiation, functions, and roles of T follicular regulatory cells in autoimmune diseases

Follicular regulatory T cell biology and its role in immune-mediated diseases

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