Immunity . . . The cooperation between Gao Yimeng/Li Huabing and others reveals the important role of m6A in natural immunity and hematopoietic development.

In higher mammals, RNA, as an intermediate carrier of genetic material, has been a research hotspot in various fields, including alternative splicing, post transcriptional processing, translation initiation, etc.and the chemical modification on such delicate RNA must have extraordinary significance.as the most common endogenous modification of RNA, N6 methyladenosine (m6A) has attracted extensive attention with the development of precise sequencing technology in recent years.previous studies have found that m6A modification plays an important role in a variety of basic biological processes and disease processes by using in vitro cell lines, various animal models and patient samples.then, what is the effect of m6A on the development of organisms under physiological conditions, and whether there is a more universal biological regulation mechanism for the existence of the RNA modification of m6A? This is a question that the whole research field has been trying to answer for a long time.on the basis of previous systematic and in-depth study of m6A in T cell differentiation (see bioart report: Nature - the first discovery of m6A modification regulating T cell homeostasis) and function (see bioart report: Li Huabing group revealed the inhibitory function of m6A on Treg cells), on June 3, 2020, Professor Li Huabing, Shanghai Institute of immunology, Shanghai Jiaotong University School of medicine, Yale University We have learned from Professor Stephanie halene, Professor Richard Flavell and other teams at home and abroad to publish the paper m6A modification prevention formation of endogenous double stranded RNAs and deleted innate immune responses during hepatopoietic development. In this paper, we found that the existence of m6A modification on RNA can maintain the self recognition of cells for autologous RNA, and the deletion of m6A will lead to the formation of abnormal endogenous double stranded RNA (dsRNA), and then cause strong innate immune response and hematopoietic system necrosis.in this study, VAV CRE; mettl3 conditional knockout mice were used to specifically knock out mettl3 of m6A in hematopoietic system, so as to observe the effect of m6A deficiency on hematopoietic system.it is difficult for researchers to obtain VAV CRE; mettl3 conditional knockout mice in previous experiments, which indicates that the loss of hematopoietic system m6A is embryonic death, and it is difficult to obtain mature mice for further research.so the researchers advanced the analysis time point to 14.5 day of embryo (E14.5), and analyzed the main hematopoietic organ of E14.5, embryonic liver.at E14.5, the survival rate of mouse embryos with different genotypes was in accordance with Mendelian genetic law, indicating that the embryos of VAV CRE; mettl3 conditional knockout mice still survived.through flow cytometry, the researchers found that in the VAV CRE; mettl3 conditional knockout embryonic liver, hematopoietic stem / progenitor cells (Lin − Sca-1 + c-kit +, LSK cells) had a significant accumulation, which could not be effectively differentiated into mature blood cells of each lineage.the transcriptome and h3k4me3 protein modified active transcription genes of LSK cells were analyzed by RNA SEQ and cut & amp; run. It was found that genes related to innate immunity and virus response were significantly up-regulated in mettl3 knockout LSK cells compared with the control group, especially the OAS family genes which can recognize and respond to virus dsRNA. The enrichment ofand H3K4me3 histone modifications at OAS genes also indicated that upregulation of OAS gene and other immune related genes was up regulation of transcription level, not because of the effect of m6A deletion on the regulation of post transcriptional regulation.under normal conditions, the RNA in cells is single stranded. DsRNA can only be generated when virus invades cells and replicates. These dsRNA will be recognized by the natural immune system as exogenous invasive RNA, and then trigger a strong immune response to eliminate the virus.in order to verify that the deletion of m6A can cause the formation of dsRNA in the absence of virus infection, the researchers used dsRNA specific antibody J2 to conduct immunofluorescence staining and RNA immunoprecipitation sequencing (J2 rip SEQ) on fetal liver cells.it is directly proved that dsRNA will be formed in cells after the deletion of m6A. Meanwhile, it is found that the transcripts forming dsRNA are RNA with more m6A modification, longer length and easier to fold under normal condition.it indicates that the presence of m6A on these RNAs can inhibit the formation of dsRNA. the researchers further examined three classic dsRNA activated innate immune pathways and found that oas-rnase L, pkr-eif2a and mda5-rig-i were activated in the fetal liver of VAV CRE; mettl3 conditional knockout mice. the activation of the corresponding signal pathway will inhibit protein synthesis and cell proliferation, and hinder hematopoietic development. and inhibiting the corresponding innate immune pathway to rescue mettl3 conditional knockout fetal liver can partially repair the phenotype of hematopoietic system necrosis caused by m6A deletion. further indicated that the deletion of m6A would lead to the formation of dsRNA and cause innate immune response and hematopoietic necrosis. at present, in addition to mettl3 knockout in embryonic stem cells (ESCs), which can maintain cells in Na ï ve state and inhibit stem cell differentiation, mettl3 knockout in most other tissue cells will cause damage, including inhibition of proliferation and differentiation, and impact on system development. this is probably related to the innate immune response caused by the deletion of m6A. However, ESCs have the characteristics of immune immunity and the expression of OAS related innate immune genes is very low, so ESCs show weak dsRNA immune response. this also shows that ESCs as the original state of stem cells is significantly different from other adult stem cells. in conclusion, this study provides a new perspective for researchers to understand the function of m6A RNA modification by using conditional knockout mouse model, reveals the universal biological significance of m6A as a natural immune regulator, and clarifies the important function of m6A in the development of hematopoietic system. and the immune and regulatory functions of m6A in other tissue systems also need to be further studied by other scholars. Dr. Gao Yimeng, Professor Richard Flavell, Professor Li Huabing, Dr. Toma tebaldi and Professor Stephanie halene are the co authors of this paper. Dr. Gao Yimeng, Dr. Song Yuanbin and Dr. Radovan vasic of Yale University are the co first authors of this paper. the completion of the work benefited from the support and selfless help of Professor Andrew Xiao, Professor Rong fan and Professor Akiko Iwasaki of Yale University. link: the Stephanie halene Laboratory of Yale University medical school recruits visiting scholars and exchange students. Professor Stephanie halene is the director of Hematology Department of Yale University Medical School, and also works at Yale cancer center, stem cell center and Yale New Haven hospital. Professor Stephanie halene has been engaged in the research of blood diseases related to MDS and AML for a long time. His research contents include splicing factor, m6A modification, humanized mouse model, etc. as a corresponding author and senior author, he has published several research papers in international first-class journals such as immunity, cancer cell, blood, nature communication, etc. the laboratory has an international research team with a happy and harmonious atmosphere, covering cell culture, mouse breeding, gene editing, credit analysis, clinical research and other research levels, and has close cooperation with many international well-known laboratories. at present, due to the needs of project progress, two visiting scholars and exchange students are specially recruited, and the visit and exchange time is not less than 8 months. the visiting scholars and exchange students before the laboratory have made outstanding achievements, obtained funds and published articles. the start time of this visit and exchange can be set as the preparation of entry materials and visa application in the early stage after the Sino US air navigation. interested students and scholars should contact Dr. Gao Yimeng by email with CV in English: yimeng.gao @ yale.edu 。 please indicate the email Title: name current school visiting scholar or exchange student. the research group of Shanghai Institute of immunology, Shanghai Jiaotong University School of medicine and Yale University Institute of immunology and metabolism Li Huabing is looking for postdoctoral and associate researcher Li Huabing, researcher of Shanghai Jiaotong University Medical School Yale University Institute of immune metabolism, researcher of Shanghai Institute of immunology, State Key Laboratory of oncogene and related genes, Shanghai Jiaotong University School of Medicine He is a part-time professor in the Institute of molecular medicine of Renji Hospital, an assistant professor and doctoral supervisor in the Department of immunology, Yale University Medical College, and is an excellent talent introduced from China and Shanghai. in the field of epigenetics and T-cell biology, researcher Li Huabing, as the first and co first / CO correspondent author, has published in nature, science, immunity, Cell Research At present, an excellent research team with postdoctoral as the main body has been established. In the station, one person has won the new doctoral program, five have won the youth fund of the NSFC, and five have won the national and municipal support awards such as Shanghai Super postdoctoral. the research group and Professor Richard Flavell of Yale University, Professor Xia Qiang of Renji Hospital and Professor Su Bing of Shanghai Institute of immunology have very close scientific research cooperation and personnel training projects. the main research direction of the research group is the function of RNA metabolism in immune cells and liver diseases and other related major diseases. At present, several promising topics are being promoted, and a series of excellent achievements are expected to be published in the near future. Talents with various backgrounds are urgently needed to undertake several important and novel tasks. especially those who have background in liver and liver disease biology, bioethics analysis, tumor biology and immunobiology are especially welcome. you are welcome to join us with favorable treatment. Please contact and consult researcher Li Huabing for details. the research group will provide each member with a pure research environment and the best academic prospects. please indicate the title: name current school postdoctoral / associate researcher application: Huabing.li @ shsmu.edu.cn  or Huabing.li @ yale.edu Plate maker: ketchup