title: Long non-coding RNA ANRIL regulates inflammatory responses as a novel component of NF-κB pathway.
abstract: Antisense Noncoding RNA in the INK4 Locus (ANRIL) is the prime candidate gene at Chr9p21, the well-defined genetic risk locus associated with multiple human diseases including coronary artery disease (CAD), while little is known regarding its role in the pathological processes. Endothelial dysfunction triggers atherosclerotic processes that are causatively linked to CAD. To evaluate the function of ANRIL in human endothelial cells (ECs), we examined ANRIL expression under pathological stimuli and found ANRIL was markedly induced by pro-inflammatory factors. Loss-of-function and chromatin immunoprecipitation approaches revealed that NF-κB mediates TNF-α induced ANRIL expression. RNA sequencing revealed that ANRIL silencing dysregulated expression of inflammatory genes including IL6 and IL8 under TNF-α treatment. We explored the regulatory mechanism of ANRIL on IL6/8 and found that Yin Yang 1 (YY1), an ANRIL binding transcriptional factor revealed by RNA immunoprecipitation, was required for IL6/8 expression under TNF-α treatment. YY1 was enriched at promoter loci of IL6/8 and ANRIL silencing impaired the enrichment, indicating a cooperation between ANRIL and YY1 in the regulation of inflammatory genes. For the first time, we establish the connection between ANRIL and NF-κB pathway and show that ANRIL regulates inflammatory responses through binding with YY1. The newly identified TNF-α-NF-κB-ANRIL/YY1-IL6/8 pathway enhances understanding of the etiology of CAD and provides potential therapeutic target for treatment of CAD.
authors.affiliation: a Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University , Beijing , 100871 , China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhou
authors.affiliation: a Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University , Beijing , 100871 , China.
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Han
authors.affiliation: b Department of Molecular and Clinical Medicine , Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg , Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Wittfeldt
authors.affiliation: c Department of Cardiolody , Affiliated Hospital of Jining Medical University , Jining , 272000 , China.
authors.forename: Jingzhi
authors.initials: J
authors.lastname: Sun
authors.affiliation: d Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University , Beijing , 100871 , China.
authors.forename: Chujun
authors.initials: C
authors.lastname: Liu
authors.affiliation: a Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University , Beijing , 100871 , China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Wang
authors.affiliation: b Department of Molecular and Clinical Medicine , Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg , Sweden.|e AstraZeneca R&D , Mölndal , Sweden.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Gan
authors.affiliation: a Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University , Beijing , 100871 , China.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Cao
authors.affiliation: a Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University , Beijing , 100871 , China.
authors.forename: Zicai
authors.initials: Z
authors.lastname: Liang
mesh_terms: D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics*; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D050986:YY1 Transcription Factor / Q000235:genetics*
chemical_list: C561518:CDKN2B antisense RNA, human; C508606:CXCL8 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D062085:RNA, Long Noncoding; D014409:Tumor Necrosis Factor-alpha; D050986:YY1 Transcription Factor; C494698:YY1 protein, human
keywords: ANRIL; NF-κB; YY1; coronary artery disease; inflammation; long non-coding RNA