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Recently, the international academic journal Cell Reports published online the latest research results titled "Setd2 determines distinct properties of intestinal ILC3 subsets to regulate intestinal immunity" by Qiu Ju's research group from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences
.
This study explores the epigenetic and transcriptional regulatory mechanisms of Setd2 on type 3 naive lymphocyte subsets
.
Setd2 (SET-domain-containing 2) is a mammalian histone H3 subunit 36 lysine (H3K36) methyltransferase, which can modify H3K36me2 to H3K36me3, and is an important regulatory molecule in epigenetics
.
Type 3 innate lymphoid cells (ILC3) are a group of innate immune cells that are abundant in the gut.
According to the surface proteins NKp46 and CCR6, they can be further divided into three subgroups, namely: NKp46+ILC3, double negative (Double negative, DN) ILC3 and CCR6+ILC3
.
The three subsets of ILC3 have phenotypic and functional heterogeneity in transcription factor expression, cytokine secretion, and spatial localization, and play important regulatory roles in diseases such as intestinal infections, inflammatory diseases, and tumors
.
Although there have been some reports on the transcriptional regulatory mechanisms underlying the differentiation of ILC3 subsets, whether and how epigenetic mechanisms affecting histone and DNA modifications are involved in the differentiation and function of ILC3s remains unclear
.
This study found that Setd2 can maintain the homeostasis of intestinal ILC3 in mice and regulate the distribution and function of ILC3 subsets, thereby affecting RORγt+ regulatory T cells (Treg) and intestinal immune responses.
.
Deletion of Setd2 leads to a decrease in the abundance of total ILC3 cells, and an increased proportion of NKp46+ILC3 subsets, high expression of cytotoxicity-related molecules (mainly Granzyme A and Granzyme C), and inhibition of melanoma growth in vivo
.
On the other hand, the CCR6+ILC3 subset depleted of Setd2 showed decreased cell number and function, accompanied by defects in the formation of solitary intestinal lymphoid tissue (SILT)
.
Adaptive immune system reconstitution experiments found that Rag1-/- mice with specific deletion of Setd2 in ILC3 were susceptible to intestinal inflammation and accompanied by defective homeostasis of RORγt+Treg
.
Treg is a subgroup of helper T cells with immunosuppressive function.
RORγt+Treg, which is relatively enriched in the intestine and can be induced by intestinal microorganisms, is a group of Treg subgroups with high expression of IL-10 and immunosuppressive function.
Intestinal inflammation plays a key role
.
The defect in homeostasis maintenance of RORγt+Treg may be caused by the decreased secretion of GM-CSF from Setd2-deficient NKp46-ILC3, which in turn leads to the decrease of CD11b+CD103+ dendritic cells (DC)
.
The researchers further found that Setd2 can regulate gene expression by affecting the chromatin accessibility of ILC3 subsets by ATAC-seq
.
This work initially explores and correlates the epigenetic and transcriptional mechanisms that regulate the differentiation and function of ILC3 subsets
.
Chang Jiali, a doctoral student at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, is the first author of the paper, and researcher Qiu Ju and researcher Li Li from the School of Biomedical Engineering, Shanghai Jiaotong University are co-corresponding authors
.
This research was completed with the strong support of Professor Hu Xiaoyu from Tsinghua University
.
Special thanks to Prof.
Qin Jun from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Prof.
Guo Xiaohuan from Tsinghua University, Dr.
Juan Carlos Zúñiga-Pflücker from University of Toronto, and Prof.
Liu Xing from Shanghai Pasteur Institute, Chinese Academy of Sciences for their help in this work
.
We also thank Dr.
Feng Dechun for his help in this work
.
The research was funded by the Ministry of Science and Technology of China, the National Natural Science Foundation of China and the Shanghai Municipal Science Committee, as well as by the Public Technology Platform and Animal Platform of the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences
.
Link to the original text: https:// Setd2 regulates the differentiation and function of various subsets of ILC3 by regulating the degree of chromatin openness, which further affects RORγt+ Treg homeostasis to maintain intestinal immune homeostasis
.
Paper link: https://
.
This study explores the epigenetic and transcriptional regulatory mechanisms of Setd2 on type 3 naive lymphocyte subsets
.
Setd2 (SET-domain-containing 2) is a mammalian histone H3 subunit 36 lysine (H3K36) methyltransferase, which can modify H3K36me2 to H3K36me3, and is an important regulatory molecule in epigenetics
.
Type 3 innate lymphoid cells (ILC3) are a group of innate immune cells that are abundant in the gut.
According to the surface proteins NKp46 and CCR6, they can be further divided into three subgroups, namely: NKp46+ILC3, double negative (Double negative, DN) ILC3 and CCR6+ILC3
.
The three subsets of ILC3 have phenotypic and functional heterogeneity in transcription factor expression, cytokine secretion, and spatial localization, and play important regulatory roles in diseases such as intestinal infections, inflammatory diseases, and tumors
.
Although there have been some reports on the transcriptional regulatory mechanisms underlying the differentiation of ILC3 subsets, whether and how epigenetic mechanisms affecting histone and DNA modifications are involved in the differentiation and function of ILC3s remains unclear
.
This study found that Setd2 can maintain the homeostasis of intestinal ILC3 in mice and regulate the distribution and function of ILC3 subsets, thereby affecting RORγt+ regulatory T cells (Treg) and intestinal immune responses.
.
Deletion of Setd2 leads to a decrease in the abundance of total ILC3 cells, and an increased proportion of NKp46+ILC3 subsets, high expression of cytotoxicity-related molecules (mainly Granzyme A and Granzyme C), and inhibition of melanoma growth in vivo
.
On the other hand, the CCR6+ILC3 subset depleted of Setd2 showed decreased cell number and function, accompanied by defects in the formation of solitary intestinal lymphoid tissue (SILT)
.
Adaptive immune system reconstitution experiments found that Rag1-/- mice with specific deletion of Setd2 in ILC3 were susceptible to intestinal inflammation and accompanied by defective homeostasis of RORγt+Treg
.
Treg is a subgroup of helper T cells with immunosuppressive function.
RORγt+Treg, which is relatively enriched in the intestine and can be induced by intestinal microorganisms, is a group of Treg subgroups with high expression of IL-10 and immunosuppressive function.
Intestinal inflammation plays a key role
.
The defect in homeostasis maintenance of RORγt+Treg may be caused by the decreased secretion of GM-CSF from Setd2-deficient NKp46-ILC3, which in turn leads to the decrease of CD11b+CD103+ dendritic cells (DC)
.
The researchers further found that Setd2 can regulate gene expression by affecting the chromatin accessibility of ILC3 subsets by ATAC-seq
.
This work initially explores and correlates the epigenetic and transcriptional mechanisms that regulate the differentiation and function of ILC3 subsets
.
Chang Jiali, a doctoral student at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, is the first author of the paper, and researcher Qiu Ju and researcher Li Li from the School of Biomedical Engineering, Shanghai Jiaotong University are co-corresponding authors
.
This research was completed with the strong support of Professor Hu Xiaoyu from Tsinghua University
.
Special thanks to Prof.
Qin Jun from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Prof.
Guo Xiaohuan from Tsinghua University, Dr.
Juan Carlos Zúñiga-Pflücker from University of Toronto, and Prof.
Liu Xing from Shanghai Pasteur Institute, Chinese Academy of Sciences for their help in this work
.
We also thank Dr.
Feng Dechun for his help in this work
.
The research was funded by the Ministry of Science and Technology of China, the National Natural Science Foundation of China and the Shanghai Municipal Science Committee, as well as by the Public Technology Platform and Animal Platform of the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences
.
Link to the original text: https:// Setd2 regulates the differentiation and function of various subsets of ILC3 by regulating the degree of chromatin openness, which further affects RORγt+ Treg homeostasis to maintain intestinal immune homeostasis
.
Paper link: https://
