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Genes specifying long non-coding RNAs (lncRNAs) occupy a large fraction of the genomes of complex organisms. The term ‘lncRNAs’ encompasses RNA polymerase I (Pol I), Pol II and Pol III transcribed RNAs, and RNAs from processed introns. The various functions of lncRNAs and their many isoforms and interleaved relationships with other genes make lncRNA classification and annotation difficult. Most lncRNAs evolve more rapidly than protein-coding sequences, are cell type specific and regulate many aspects of cell differentiation and development and other physiological processes. Many lncRNAs associate with chromatin-modifying complexes, are transcribed from enhancers and nucleate phase separation of nuclear condensates and domains, indicating an intimate link between lncRNA expression and the spatial control of gene expression during development. lncRNAs also have important roles in the cytoplasm and beyond, including in the regulation of translation, metabolism and signalling. lncRNAs often have a modular structure and are rich in repeats, which are increasingly being shown to be relevant to their function. In this Consensus Statement, we address the definition and nomenclature of lncRNAs and their conservation, expression, phenotypic visibility, structure and functions. We also discuss research challenges and provide recommendations to advance the understanding of the roles of lncRNAs in development, cell biology and disease.This Consensus Statement addresses the definition, nomenclature and classification of long non-coding RNAs, and provides a shared viewpoint on their features and functions. The authors also discuss research challenges and provide recommendations to advance our understanding of long non-coding RNAs.

Dosage compensation, which is achieved by X-chromosome inactivation (XCI) in female mammals, ensures balanced X-linked gene expression levels between the sexes. Although eutherian mammals commonly display random XCI in embryonic and adult tissues, imprinted XCI has also been identified in extraembryonic tissues of mouse, rat, and cow. Little is known about XCI in pigs. Here, we sequenced the porcine XIST gene and identified an insertion/deletion mutation between Asian- and Western-origin pig breeds. Allele-specific analysis revealed biallelic XIST expression in porcine ICSI blastocysts. To investigate the XCI pattern in porcine placentas, we performed allele-specific RNA sequencing analysis on individuals from reciprocal crosses between Duroc and Rongchang pigs. Our results were the first to reveal that random XCI occurs in the placentas of pigs. Next, we investigated the H3K27me3 histone pattern in porcine blastocysts, showing that only 17–31.8% cells have attained XCI. The hypomethylation status of an important XIST DMR (differentially methylated region) in gametes and early embryos demonstrated that no methylation is pre-deposited on XIST in pigs. Our findings reveal that the XCI regulation mechanism in pigs is different from that in mice and highlight the importance of further study of the mechanisms regulating XCI during early porcine embryo development.

Females have a greater immunological advantage than men, yet they are more prone to autoimmune disorders. The basis for this sex bias lies in the X chromosome, which contains many immunity-related genes. Femalemammals use X chromosome inactivation (XCI) to generate a transcriptionally silent inactive X chromosome (Xi) enriched with heterochromatic modifications and XIST/Xist RNA, which equalizes gene expression between the sexes. Here, we examine the maintenance of XCI in lymphocytes from females in mice and humans. Strikingly, we find that mature naïve T and B cells have dispersed patterns of XIST/Xist RNA, and they lack the typical heterochromatic modifications of the Xi. In vitro activation of lymphocytes triggers the return of XIST/Xist RNA transcripts and some chromatin marks (H3K27me3, ubiquitin-H2A) to the Xi. Single-cell RNA FISH analysis of female T cells revealed that the X-linked immunity genes CD40LG and CXCR3 are biallelically expressed in some cells. Using knockout and knockdown approaches, we find that Xist RNA-binding proteins, YY1 and hnRNPU, are critical for recruitment of XIST/Xist RNA back to the Xi. Furthermore, we examined B cells from patients with systemic lupus erythematosus, an autoimmune disorder with a strong female bias, and observed different XIST RNA localization patterns, evidence of biallelic expression of immunity-related genes, and increased transcription of these genes. We propose that the Xi in female lymphocytes is predisposed to become partially reactivated and to overexpress immunity-related genes, providing the first mechanistic evidence to our knowledge for the enhanced immunity of females and their increased susceptibility for autoimmunity.

X-inactive specific transcript (Xist) is a main regulator of X chromosome inactivation in mammals, which silences most genes on X chromosome in a cis way. Xist is a kind of lncRNA, which cannot encode the transcript of protein. In addition, Xist RNA mediates the X chromosome inactivation (XCI) process to achieve dose compensation between the sexes. Recent studies have identified that Xist RNA regulates gene expression by recruiting factors/complexes to modify potential chromatin, which were involved in diseases such as neuroinflammation, autoimmune diseases and cancers. In this paper, the research progress of Xist RNA causing a series of diseases in mammalian cells is reviewed, which makes it a potential target for treating human diseases and provides a new direction for further study of diseases.

Systemic lupus erythematous (SLE) is a female-predominant disease characterized by autoimmune B cells and pathogenic autoantibody production. Individuals with two or more X chromosomes are at increased risk for SLE, suggesting that X-linked genes contribute to the observed sex bias of this disease. To normalize X-linked gene expression between sexes, one X in female cells is randomly selected for transcriptional silencing through X-chromosome inactivation (XCI), resulting in allele-specific enrichment of epigenetic modifications, including histone methylation and the long noncoding RNA XIST/Xist on the inactive X (Xi). As we have previously shown that epigenetic regulation of the Xi in female lymphocytes from mice is unexpectedly dynamic, we used RNA fluorescence in situ hybridization and immunofluorescence to profile epigenetic features of the Xi at the single-cell level in human B cell subsets from pediatric and adult SLE patients and healthy controls. Our data reveal that abnormal XCI maintenance in B cells is a feature of SLE. Using single-cell and bulk-cell RNA sequencing datasets, we found that X-linked immunity genes escape XCI in specific healthy human B cell subsets and that human SLE B cells exhibit aberrant expression of X-linked genes and XIST RNA interactome genes. Our data reveal that mislocalized XIST RNA, coupled with a dramatic reduction in heterochromatic modifications at the Xi in SLE, predispose for aberrant X-linked gene expression from the Xi, thus defining a genetic and epigenetic pathway that affects X-linked gene expression in human SLE B cells and likely contributes to the female bias in SLE.

Long non-coding RNAs (lncRNAs) play an important role in the development of bone-related diseases. This study was conducted to investigate the role and mechanism of lncRNA X inactive specific transcript (XIST) in the occurrence of cervical ossification of the posterior longitudinal ligament (OPLL). Here, primary human ligament fibroblasts cells (LFCs) were isolated from 30 cases of OPLL and 30 normal cervical posterior longitudinal ligament (non-OPLL) tissues to perform the qPCR and Western blot assay. We found that the mRNA level of lncRNA XIST was significantly increased in OPLL LFCs compared to non-OPLL LFCs. By bioinformatics analysis, we found that lncRNA XIST has four binding sites for miR-17-5p and found that the mRNA level of miR-17-5p was also significantly decreased in OPLL LFCs compared to non-OPLL LFCs. Since AHNAK is the target gene of miR-17-5p, we further found that the expression of AHNAK was significantly reduced in non-OPLL LFCs after being transfected with miR-17-5p mimic. The qPCR results showed that the mRNA expressions of BMP2 and Runx2 were significantly decreased. After being transfected with lncRNA XIST siRNA in the non-OPLL LFCs, the mRNA levels of lncRNA XIST, AHNAK, BMP2, and Runx2 were significantly decreased and the phosphorylated protein of Smad1/5/8 was reduced. After being cultured by mechanical vibration, the mRNA levels of lncRNA XIST, AHNAK, BMP2, Runx2, COL1, OC, OPN, and Phospho1 were significantly increased, but the mRNA expression of miR-17-5p was significantly decreased. The expression of phosphorylated Smad1/5/8 protein was also significantly increased. Together, this study was the first to determine that XIST gene inhibition plays an important role in the occurrence of cervical OPLL, through the mechanism of regulation of miR-17-5P/AHNAK/BMP2 signaling pathway. Thus, XIST may be a potential target that could be modulated for the treatment of cervical OPLL.

The limited knowledge of genomic noncoding and regulatory regions has restricted our ability to decipher the genetic mechanisms underlying complex traits in pigs. In this study, we characterized the spatiotemporal landscape of putative enhancers and promoters and their target genes by combining H3K27ac-targeted ChIP-Seq and RNA-Seq in fetal (prenatal days 74–75) and adult (postnatal days 132–150) tissues (brain, liver, heart, muscle and small intestine) sampled from Asian aboriginal Bama Xiang and European highly selected Large White pigs of both sexes. We identified 101,290 H3K27ac peaks, marking 18,521 promoters and 82,769 enhancers, including peaks that were active across all tissues and developmental stages (which could indicate safe harbor locus for exogenous gene insertion) and tissue- and developmental stage-specific peaks (which regulate gene pathways matching tissue- and developmental stage-specific physiological functions). We found that H3K27ac and DNA methylation in the promoter region of the XIST gene may be involved in X chromosome inactivation and demonstrated the utility of the present resource for revealing the regulatory patterns of known causal genes and prioritizing candidate causal variants for complex traits in pigs. In addition, we identified an average of 1,124 super-enhancers per sample and found that they were more likely to show tissue-specific activity than ordinary peaks. We have developed a web browser to improve the accessibility of the results ( http://segtp.jxau.edu.cn/pencode/?genome=susScr11 ).

Background Activation of CXCL12/CXCR4 axis has been found to be associated with invasion and metastasis in many cancers. However, the underlying mechanism remains elusive. Increasing data highlight that non-coding RNAs are linked to CRC progression. Methods The effects of CXCR4 were investigated using villin-CXCR4 transgenic mice model by flow cytometry assay, immunohistochemistry, and Western blot. The mechanism was explored through bioinformatics, luciferase reporter assay and RNA immunoprecipitation assay. Results We found that high CXCR4 expression exacerbated colitis-associated cancer in villin-CXCR4 transgenic mice. CXCR4 +/− Apc min/+ compound mutant mice demonstrated higher colorectal tumorigenesis than Apc min/+ mice. Furthermore, overexpression of CXCR4 was found to promote the epithelial-mesenchymal transition (EMT) and infiltration of myeloid-derived suppressor cells (MDSCs) and macrophages in colonic tissue, accelerating colitis-associated and Apc mutation-driven colorectal tumorigenesis and progression. Notably, miR-133a-3p was found to be significantly decreased in HCT116 cells overexpressing CXCR4 by miRNA sequencing. miR-133a-3p was proved to target RhoA, which is involved in cytoskeletal reorganization that drive cell motility. Importantly, CXCL12/CXCR4-induced upregulation of lncRNA XIST functioned as a ceRNA to sponge miR-133a-3p, thereby liberating the repression of RhoA by miR-133a-3p. The negative correlation of miR-133a-3p with RhoA was also confirmed in human CRC tissues and CXCR4 +/− mice. Conclusions Our findings revealed the critical role of CXCR4 in promoting progression of inflammatory colorectal cancer through recruiting immunocytes and enhancing cytoskeletal remodeling by lncRNA XIST/ miR-133a-3p/ RhoA signaling. These results provide novel potential therapeutic targets for hindering CXCL12/CXCR4-induced CRC progression.

Background Long non-coding RNAs (lncRNAs) play a functional role in the progression of prostate cancer (PCa). However, the molecular mechanism, expression, or function of the lncRNA XIST in PCa is not well understood. Therefore, the major goal of this study was to investigate the involvement of XIST in PCa. Methods We used the The Cancer Genome Atlas (TCGA) database to conduct a pan-cancer bioinformatics analysis of XIST and identified that it may play an important role in prostate cancer. This finding was verified using clinical samples and in vitro assays. Finally, we constructed an XIST ceRNA network for prostate cancer. Results Our in vitro and in vivo results showed that the XIST gene expression level was higher in PCa derived cells and tissues compared to that in normal cells and tissues. XIST gene expression level was positively correlated with the invasion and proliferation of tumour cells. Furthermore, the downregulation of XIST inhibited the growth of subcutaneous 22Rv1 xenografts in nude mice. In addition, we constructed a XIST ceRNA network. Consistent with previous studies, we found that the role of XIST is mediated through via sponges, such as miRNA -96-5p, miRNA -153-3p, and miRNA-182-5p. Conclusion High expression level of XIST can lead to enhanced carcinogenicity in PCa. Therefore, XIST has the potential to be used as a prognostic marker and may become a new research focus for the treatment of PCa.