Setd2 determines distinct properties of intestinal ILC3 subsets to regulate intestinal immunity

Chang, Jiali; Ji, Xiaojuan; Deng, Tian; Qiu, Jinxin; Ding, Zhaoyun; Zhao, Li; Ma, Yonggang; Hu, Xiaoyu; Li, Li; Qiu, Ju

doi:10.1016/j.celrep.2022.110530

Cited by 14 publications

(13 citation statements)

References 82 publications

(132 reference statements)

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“…Moreover, several in vivo studies showed that the differentiation of DCs was regulated by ILC3s. 47,48 In the current study, the levels of cDC1s were positively correlated with the frequency of ILC3s and CCR6 + ILC3s. Research has suggested that ILC3-derived GM-CSF interacts with intestinal DCs to facilitate the production of retinoic acid and interleukin-10 (IL-10), which in turn contributes to intestinal immune homeostasis.…”

Section: Discussionsupporting

confidence: 56%

Reduced type 3 innate lymphoid cells related to worsening kidney function in renal dysfunction

Pan

Liu

Zhuang

et al. 2023

Exp Biol Med (Maywood)

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Intestinal mucosa barrier injury and immunity imbalance contribute to chronic kidney disease (CKD) progression. Type 3 innate lymphoid cells (ILC3s) are essential for normal intestinal homeostasis. Nevertheless, the relationship between ILC3s and CKD remains largely unknown. The aim of this study was to investigate the relationship linking ILC3s to clinical indicators among patients with renal dysfunction. The levels of circulating ILC3s and dendritic cells, as well as their subsets, in patients with renal dysfunction and healthy controls were determined through flow cytometry. The levels of human plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured using enzyme-linked immunosorbent assay. Renal function was evaluated by measuring the estimated glomerular filtration rate (eGFR), as well as the levels of serum creatinine, blood urea nitrogen (BUN), and uric acid. The results revealed that the proportion of peripheral ILC3s was significantly decreased in patients with renal dysfunction. This reduction was positively associated with the levels of eGFR, and inversely associated with the levels of BUN and uric acid. Similarly, the percentage of circulating C-C motif chemokine receptor 6-positive (CCR6 +) ILC3s was also obviously reduced, and demonstrated positive and negative associations with the levels of eGFR and BUN, respectively. Furthermore, the levels of CCR6 + ILC3s correlated positively with those of GM-CSF, as well as type 1 conventional dendritic cells (cDC1s), which also decreased in parallel with kidney function. Thus, the reduction of ILC3s, particularly CCR6 + ILC3s, was related to worsening kidney function in patients with renal dysfunction. This effect may delay renal function impairment by regulating cDC1s via the secretion of GM-CSF, indicating that CCR6 + ILC3s may serve as efficient biomarkers for evaluating kidney function.

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Section: Discussionsupporting

confidence: 56%

Reduced type 3 innate lymphoid cells related to worsening kidney function in renal dysfunction

Pan

Liu

Zhuang

et al. 2023

Exp Biol Med (Maywood)

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“…The methyltransferase catalyzing the formation of H3K36me3 in histone H3, SETD2, has long been viewed as a tumor suppressor in some types of cancer ( Duns et al., 2010 ). However, recent study unraveled indirect tumor promoting property of SETD2 in negatively regulating the tumor suppressive-like activity of the NK cells and/or altering the subpopulation of the group 3 innate lymphoid cells (ILC3s) ( Chang et al., 2022 ). Knockout of SETD2 reduced the expression of several key inflammatory cytokines in ILC3, including IL-17A, IL-17F, NRP1, CCR6, etc, which will also weaken the pro-tumorigenic environment of the cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Deletion of mdig enhances H3K36me3 and metastatic potential of the triple negative breast cancer cells

Thakur¹,

Qiu²,

Zhang³

et al. 2022

iScience

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“…In addition, our recent studies reported that SETD2 plays important roles in intestinal immunity, suppressing intestinal inflammation, maternal epigenome, genomic imprinting and embryonic development, bone marrow mesenchymal stem cell differentiation, sperm development, and V(D)J recombination in normal lymphocyte development. [23][24][25][26][27][28][29][30][31] Moreover, SETD2 loss led to pancreatic carcinogenesis through preprint (which was not certified by peer review) is the author/funder. All rights reserved.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, our recent studies reported that SETD2 plays important roles in intestinal immunity, suppressing intestinal inflammation, maternal epigenome, genomic imprinting and embryonic development, bone marrow mesenchymal stem cell differentiation, sperm development, and V(D)J recombination in normal lymphocyte development. [23][24][25][26][27][28][29][30][31] Moreover, SETD2 loss led to pancreatic carcinogenesis through epigenetic dysregulation of Fbxw7. Based on the polycystic kidney disease (PKD) model caused by the oncogene MYC, SETD2 deficiency accelerates the transition from polycystic kidney disease (PKD) to RCC by regulating β-catenin activity on transcriptional and post-transcriptional levels.…”

Section: Discussionmentioning

confidence: 99%

“…Our recent studies also reported that SETD2 plays important role in developmental areas and disease occurrence. [23][24][25][26][27][28][29][30][31] Notably, SETD2 deficiency accelerates the transition from polycystic kidney disease (PKD) to renal cell carcinoma (RCC) by regulating β-catenin activity. 31 However, the role of SETD2 in renal fibrosis remains still unknown.…”

Section: Introductionmentioning

confidence: 99%

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SETD2 deficiency promotes renal fibrosis through the TGF-β/Smad signaling pathway in the absence of VHL

Liu

Zhu

et al. 2022

Preprint

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Renal fibrosis is the final development pathway and the most common pathological manifestation of chronic kidney disease. An important intrinsic cause of renal fibrosis is epigenetic alterations. SET domain containing 2 (SETD2) is the sole histone H3K36 trimethyltransferase, catalyzing H3K36 dimethylation to trimethylation. There is evidence that SETD2-mediated epigenetic alterations are implicated in many diseases. However, it is unclear what role SETD2 plays in the development of renal fibrosis. Clinical data indicate that SETD2 is lowly expressed in patients with renal fibrosis. Here, we established genetically engineered mice with SETD2 and VHL deficiency. SETD2 deficiency leads to severe renal fibrosis in VHL-deficient mice. Mechanically, SETD2 maintains the transcriptional level of Smad7, a negative feedback factor of the TGF-β/Smad signaling pathway, thereby preventing the activation of the TGF-β/Smad signaling pathway. Deletion of SETD2 leads to reduced smad7 expression, which results in activation of the TGF-β/Smad signaling pathway and ultimately fibrosis in the absence of VHL. Our findings reveal the role of SETD2-mediated H3K36me3 of Smad7 in regulating the TGF-β/Smad signaling pathway in renal fibrogenesis. Thus, our study provides innovative insights into SETD2 as a potential therapeutic target for the treatment of renal fibrosis.

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Setd2 determines distinct properties of intestinal ILC3 subsets to regulate intestinal immunity

Cited by 14 publications

References 82 publications

Reduced type 3 innate lymphoid cells related to worsening kidney function in renal dysfunction

Reduced type 3 innate lymphoid cells related to worsening kidney function in renal dysfunction

Deletion of mdig enhances H3K36me3 and metastatic potential of the triple negative breast cancer cells

SETD2 deficiency promotes renal fibrosis through the TGF-β/Smad signaling pathway in the absence of VHL

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