Dicer-independent snRNA/snoRNA-derived nuclear RNA 3 regulates tumor-associated macrophage function by epigenetically repressing inducible nitric oxide synthase transcription  

作　　者：Yang Shi Qingzhu Shi Qicong Shen Qian Zhang Xuetao Cao 

机构地区：[1]Institute of Immunology,Zhejiang University School of Medicine,Hangzhou,Zhejiang 310058,P.R.China [2]National Key Laboratory of Medical Immunology&Institute of Immunology,Second Military Medical University,Shanghai 200433,P.R.China [3]Department of Immunology,Institute of Basic Medical Research,Chinese Academy of Medical Sciences,Beijing 100005,P.R.China

出　　处：《Cancer Communications》2021年第2期140-153,共14页癌症通讯（英文）

基　　金：This work was supported by the National Natural Science Foundation of China(81922032,31900660,81788101);the Young Elite Scientist Sponsorship Program by CAST(2018QNRC001).

摘　　要：Background:Small RNAs(sRNAs)extensively mediate gene-specific chromatin regulation in lower organisms.As a dominant type of functional sRNAs in mature mammals,microRNAs mainly regulate gene expression at posttranscription level in the cytoplasm.Currently,whether there exists a type of nuclear-localized sRNAs mediating gene-specific epigenetic regulation in mature mammalian cells remains largely unclear.Here,we profiled sRNAs enriched in the nucleus and investigated their function in mediating genespecific epigenetic regulation in anti-tumor immunity.Methods:We established cytoplasmic and nuclear transcriptomes of sRNAs of dendritic cells(DCs)using high-throughput sequencing.Transcription abundances of sRNAs and mRNAs were analyzed by reverse transcriptionquantitative polymerase chain reaction(RT-qPCR)assay.The associations between sRNAs and Argonaute(AGO)proteins were detected by RNA immunoprecipitation analysis.Synthesized sRNAs and locked nucleic acid(LNA)-modified sRNA inhibitors were used to screen the function of sRNAs in innate immune cells.The effect of sRNA on the enrichment of either chromatin remodeler or histone modification at the gene promoter was analyzed by chromatin immunoprecipitation(ChIP)-qPCR assay.Chromatin accessibility qPCR assay was used to detect the accessibility of gene promoters.A B16 melanomabearing mouse model was established to determine the function of sRNAs in tumor-associated macrophages(TAMs)and their effect on tumor growth.Results:We identified a new class of nucleus-localized sRNAs,named snRNA/snoRNA-derived nuclear RNAs(sdnRNAs).Some sdnRNAs were Dicerindependent and had no association with Argonaute proteins.sdnRNA-3,the most abundant Dicer-independent sdnRNAs identified in our analysis,was selected as a representative to examine the biological function of sdnRNAs.sdnRNA-3 selectively inhibited the transcription of Nos2 in macrophages during innate immune response by repressing the chromatin accessibility at Nos2 gene promoter.sdnRNA-3 promoted the enrichments of repressive

关 键 词：dendritic cells iNOS Mi-2β NOS2 sdnRNA small RNAs tumor-associated macrophages 

分 类 号：R73[医药卫生—肿瘤]