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Rewiring of chromatin state and gene expression by transposable elements

DEVELOPMENT GROWTH & DIFFERENTIATION 2021年第4-5期63卷 262-273页

作者： Ohtani, Hitoshi Iwasaki, Yuka W. Nagoya Univ Grad Sch Bioagr Sci Dept Anim Sci Lab Genome & Epigenome Dynam Nagoya Aichi Japan Keio Univ Sch Med Dept Mol Biol Tokyo 1608582 Japan Japan Sci & Technol Agcy JST Precursory Res Embryon Sci & Technol PRESTO Saitama Japan

Transposable elements form a major fraction of the genome in various eukaryotic species. Although deleterious effects of transpositions within the genome have been reported, recent findings suggest that transposable elements can function as novel regulatory elements to fine-tune gene expression. Transposable elements can impact the chromatin state through processes such as heterochromatin formation, enhancer-promoter interactions, and chromatin boundary formation, mainly because of the functions of chromatin-based pathways that regulate the expression of transposable elements via DNA methylation and repressive histone modification. Therefore, transposable elements can rewire the chromatin state and gene expression depending on their insertions. Here, we review the findings that reveal the role of transposable elements as modifiers of the chromatin state and gene expression as well as the molecular mechanisms capable of inducing these changes.

关键词： transposable element enhancer transcriptional regulation non-coding rna chromatin state

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The epigenetics of keloids

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EXPERIMENTAL DERMATOLOGY 2021年第8期30卷 1099-1114页

作者： Stevenson, Andrew W. Deng, Zhenjun Allahham, Amira Prele, Cecilia M. Wood, Fiona M. Fear, Mark W. Univ Western Australia Sch Biomed Sci Fac Hlth & Med Sci Burn Injury Res Unit Perth WA Australia Univ Western Australia Sch Med Ear Sci Ctr Perth WA Australia Burns Serv Western Australia Princess Margaret Hosp Children & Fiona Stanley Hosp Perth WA Australia Univ Western Australia Inst Resp Hlth Perth WA Australia

Keloid scarring is a fibroproliferative disorder of the skin with unknown pathophysiology, characterised by fibrotic tissue that extends beyond the boundaries of the original wound. Therapeutic options are few and commonly ineffective, with keloids very commonly recurring even after surgery and adjunct treatments. Epigenetics, defined as alterations to the DNA not involving the base-pair sequence, is a key regulator of cell functions, and aberrant epigenetic modifications have been found to contribute to many pathologies. Multiple studies have examined many different epigenetic modifications in keloids, including DNA methylation, histone modification, micrornas and long non-coding rnas. These studies have established that epigenetic dysregulation exists in keloid scars, and successful future treatment of keloids may involve reverting these aberrant modifications back to those found in normal skin. Here we summarise the clinical and experimental studies available on the epigenetics of keloids, discuss the major open questions and future perspectives on the treatment of this disease.

关键词： epigenetics histone modification keloid methylation non-coding rna

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Molecular interactions of miR-338 during tumor progression and metastasis

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CELLULAR & MOLECULAR BIOLOGY LETTERS 2021年第1期26卷 1-24页

作者： Moghbeli, Meysam Mashhad Univ Med Sci Sch Med Dept Med Genet & Mol Med Mashhad Razavi Khorasan Iran

Background Cancer, as one of the main causes of human deaths, is currently a significant global health challenge. Since the majority of cancer-related deaths are associated with late diagnosis, it is necessary to develop minimally invasive early detection markers to manage and reduce mortality rates. Micrornas (mirnas), as highly conserved non-coding rnas, target the specific mrnas which are involved in regulation of various fundamental cellular processes such as cell proliferation, death, and signaling pathways. Mirnas can also be regulated by long non-coding rnas (lncrnas) and circular rnas (circrnas). They are highly stable in body fluids and have tumor-specific expression profiles, which suggest their suitability as efficient non-invasive diagnostic and prognostic tumor markers. Aberrant expression of miR-338 has been widely reported in different cancers. It regulates cell proliferation, migration, angiogenesis, and apoptosis in tumor cells. Main body In the present review, we have summarized all miR-338 interactions with other non-coding rnas (ncrnas) and associated signaling pathways to clarify the role of miR-338 during tumor progression. Conclusions It was concluded that miR-338 mainly functions as a tumor suppressor in different cancers. There were also significant associations between miR-338 and other ncrnas in tumor cells. Moreover, miR-338 has a pivotal role during tumor progression using the regulation of WNT, MAPK, and PI3K/AKT signaling pathways. This review highlights miR-338 as a pivotal ncrna in biology of tumor cells.

关键词： non-coding rna Microrna MiR-338 Cancer Biomarker

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The Emerging Clinical Application of m6A rna Modification in Inflammatory Bowel Disease and Its Associated Colorectal Cancer

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JOUrnaL OF INFLAMMATION RESEARCH 2021年 14卷 3289-3306页

作者： Xu, Xinwei Huang, Jintu Ocansey, Dickson Kofi Wiredu Xia, Yuxuan Zhao, Zihan Xu, Zhiwei Yan, Yongmin Zhang, Xu Mao, Fei Jiangsu Univ Dept Clin Lab Diagnost Key Lab Med Sci & Lab Med Jiangsu Prov Sch Med Zhenjiang 212013 Jiangsu Peoples R China Nantong Univ Clin Lab Dept Peoples Hosp Danyang Affiliated Danyang Hosp Zhenjiang 212300 Jiangsu Peoples R China Univ Cape Coast Dept Clin Lab Diagnost Directorate Univ Hlth Serv Cape Coast Ghana

Methylation, first proposed in DNAs, but later found in rnas, serves as one of the most widespread epigenetic modifications in eukaryotes, where N6-methyladenosine (m6A) modification has been found to play an important role in a variety of cancers including colorectal cancer (CRC). Under the action of various enzymes and proteins, the regulatory role of m6A in rnas and immune cells has also been gradually realized. This paper reviews the general biogenesis and effects of m6A, and its emerging crucial role in intestinal mucosal immunity via the regulation of rnas and immune cells, and thus closely related to the occurrence and development of inflammatory bowel disease (IBD) and CRC. m6A-related genes and regulatory factors are expected to be potential predictive markers and therapeutic targets.

关键词： N6-methyladenosine inflammatory bowel disease colorectal cancer non-coding rna intestinal mucosal immunity

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Novel Genetic and Epigenetic Biomarkers of Prognostic and Predictive Significance in Stage II/III Colorectal Cancer

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MOLECULAR THERAPY 2021年第2期29卷 587-596页

作者： Luo, Xiao-Jing Zhao, Qi Liu, Jia Zheng, Jia-Bo Qiu, Miao-Zhen Ju, Huai-Qiang Xu, Rui-Hua Sun Yat Sen Univ Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Canc Ctr 651 Dongfeng East Rd Guangzhou 510060 Peoples R China

The therapeutic strategies of stage II/III colorectal cancer (CRC) patients after curative surgery remain controversial. In the clinical decision-making process, oncologists need to answer questions such as whether adjuvant chemotherapy is necessary or which therapeutic regimen should be given to each patient. At present, whether adjuvant chemotherapy should be applied is primarily based on histopathological features and clinical risk factors. However, only a fraction of patients can benefit from it. More rigorous stratifying biomarkers are urgently needed to help further distinguishing these populations of patients. Recent progress in next-generation sequencing and high-throughput technologies has greatly promoted biomarker discovery as well as our understanding of the underlying mechanisms in CRC. Novel genetic and epigenetic biomarkers that are associated with prognosis or therapeutic responses have emerged. In this review, we discuss the strategies of biomarker discovery and summarize the status and assess the utility of previously published biomarkers in CRC.Y

关键词： colorectal cancer biomarker prognostic predictive genomic transcriptomic epigenetic non-coding rna lncrna mirna circrna

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OncomiRs miR-106a and miR-17 negatively regulate the nucleoside-derived drug transporter hCNT1

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CELLULAR AND MOLECULAR LIFE SCIENCES 2021年第23期78卷 7505-7518页

作者： Boces-Pascual, Clara Mata-Ventosa, Aida Martin-Satue, Mireia Boix, Loreto Gironella, Meritxell Pastor-Anglada, Marcal Perez-Torras, Sandra Univ Barcelona IBUB Inst Biomed Dept Biochem & Mol Biomed Mol Pharmacol & Expt Therapeut Barcelona Spain Inst Salud Carlos III Ctr Invest Biomed Red Enfermedades Hepat & Digest Madrid Spain Inst Recerca St Joan Deu IR SJD CERCA Barcelona Spain Univ Barcelona Fac Med & Hlth Sci Dept Pathol & Expt Therapeut Campus Bellvitge Barcelona Spain Biomed Res Inst Bellvitge IDIBELL Oncobell Program Barcelona Spain Inst Salud Carlos III Ctr Invest Biomed Red Canc CIBERONC Madrid Spain Univ Barcelona Inst Invest Biomed August Pi & Sunyer IDIBAPS Fundacio Clin Recerca Biomed FCRBHosp Clin Barce Barcelona Clin Liver Canc BCLC GrpLiver Unit Barcelona Spain Hosp Clin Barcelona Inst Invest Biomed August Pi & Sunyer IDIBAPS Gastrointestinal & Pancreat Oncol Grp Barcelona Spain

High-affinity uptake of natural nucleosides as well as nucleoside derivatives used in anticancer therapies is mediated by human concentrative nucleoside transporters (hCNTs). hCNT1, the hCNT family member that specifically transports pyrimidines, is also a transceptor involved in tumor progression. In particular, oncogenesis appears to be associated with hCNT1 downregulation in some cancers, although the underlying mechanisms are largely unknown. Here, we sought to address changes in colorectal and pancreatic ductal adenocarcinoma-both of which are important digestive cancers-in the context of treatment with fluoropyrimidine derivatives. An analysis of cancer samples and matching non-tumoral adjacent tissues revealed downregulation of hCNT1 protein in both types of tumor. Further exploration of the putative regulation of hCNT1 by micrornas (mirnas), which are highly deregulated in these cancers, revealed a direct relationship between the oncomiRs miR-106a and miR-17 and the loss of hCNT1. Collectively, our findings provide the first demonstration that hCNT1 inhibition by these oncomiRs could contribute to chemoresistance to fluoropyrimidine-based treatments in colorectal and pancreatic cancer. [GRAPHICS] .

关键词： non-coding rna Nucleoside analog Nucleoside transporter CNT1 Chemoresistance

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Investigation of circular rnas in an ectoparasitic mite Varroa destructor (Acarina: Varroidae) of the honey bee

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PARASITOLOGY RESEARCH 2021年第2期120卷 715-723页

作者： Lin, Zheguang Xu, Hao Su, Xiaoling Ke, Yalu Wang, Wei Li, Yujiao Zhuang, Mingliang Chen, Heng Liu, Yibing Wang, Kang Chen, Guohong Ji, Ting Yangzhou Univ Coll Anim Sci & Technol Apicultural Res Inst Yangzhou 225009 Jiangsu Peoples R China Jinhua Acad Agr Sci Jinhua 321017 Zhejiang Peoples R China Wuzhong Anim Hlth Supervis Inst Suzhou 215100 Peoples R China Shandong Apiculture Breeding Improved Varieties & Tai An 271000 Shandong Peoples R China Apicultural Sci Inst Jilin Prov Jilin 132108 Jilin Peoples R China

Circular rnas (circrnas) are a large class of non-protein-coding transcripts that are involved in a diverse spectrum of regulatory mechanisms across a broad range of biological processes. To date, however, few studies on circrnas have investigated their role in the biology of invertebrate parasites. The ectoparasitic mite Varroa destructor is perceived as the principal biotic threat towards global honey bee health. This parasite cannot be sustainably controlled partially due to the lack of knowledge about its basic molecular biology. In this paper, we unveil the circrna profile of V. destructor for the first time and report the sources, distribution, and features of the identified circrnas. Exonic, intronic, exon-intron, and intergenic circrnas were discovered and exon-intron circrnas were the most abundant within the largest spliced length. Three hundred and eighty-six (8.3%) circrnas were predicted to possess translational potential. Eleven circrnas, derived from six parental genes, exhibited strong bonds with mirnas as sponges, suggesting an efficient post-transcriptional regulation. GO term and KEGG pathway enrichment analyses of the parental genes of the identified circrnas showed that these non-coding rnas were mainly engaged in protein processing, signal transduction, and various metabolism processes. To our knowledge, this is the first catalog of a circrna profile of parasitiformes species, which reveals the prevalence of circrnas in the parasite and provides biological insights for future genetic studies on this ubiquitous parasitic mite.

关键词： Circular rna Varroa destructor Honey bee non-coding rna Ectoparasitic mite

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Transcriptional and post-transcriptional regulation of the pregnane X receptor: a rationale for interindividual variability in drug metabolism

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ARCHIVES OF TOXICOLOGY 2021年第1期95卷 11-25页

作者： Smutny, Tomas Hyrsova, Lucie Braeuning, Albert Ingelman-Sundberg, Magnus Pavek, Petr Charles Univ Prague Fac Pharm Hradec Kralove Dept Pharmacol & Toxicol Akad Heyrovskeho 1203 Hradec Kralove 50005 Czech Republic German Fed Inst Risk Assessment Dept Food Safety Max Dohrn Str 8-10 D-10589 Berlin Germany Karolinska Inst Dept Physiol & Pharmacol Sect Pharmacogenet Solna Vagen 9 S-17165 Stockholm Sweden

The pregnane X receptor (PXR, encoded by the NR1I2 gene) is a ligand-regulated transcription factor originally described as a master regulator of xenobiotic detoxification. Later, however, PXR was also shown to interact with endogenous metabolism and to be further associated with various pathological states. This review focuses predominantly on such aspects, currently less covered in literature, as the control of PXR expression per se in the context of inter-individual differences in drug metabolism. There is growing evidence that non-coding rnas post-transcriptionally regulate PXR. Effects on PXR have especially been reported for micrornas (mirnas), which include miR-148a, miR-18a-5p, miR-140-3p, miR-30c-1-3p and miR-877-5p. Likewise, mirnas control the expression of both transcription factors involved in PXR expression and regulators of PXR function. The impact of NR1I2 genetic polymorphisms on mirna-mediated PXR regulation is also discussed. As revealed recently, long non-coding rnas (lncrnas) appear to interfere with PXR expression. Reciprocally, PXR activation regulates non-coding rna expression, thus comprising another level of PXR action in addition to the direct transactivation of protein-coding genes. PXR expression is further controlled by several transcription factors (cross-regulation) giving rise to different PXR transcript variants. Controversies remain regarding the suggested role of feedback regulation (auto-regulation) of PXR expression. In this review, we comprehensively summarize the mirna-mediated, lncrna-mediated and transcriptional regulation of PXR expression, and we propose that deciphering the precise mechanisms of PXR expression may bridge our knowledge gap in inter-individual differences in drug metabolism and toxicity.

关键词： Pregnane X receptor Gene expression non-coding rna microrna Post-transcriptional regulation

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Characterization of circular rna transcriptomes in psoriasis and atopic dermatitis reveals disease-specific expression profiles

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EXPERIMENTAL DERMATOLOGY 2021年第8期30卷 1187-1196页

作者： Moldovan, Liviu I. Tsoi, Lam C. Ranjitha, Uppala Hager, Henrik Weidinger, Stephen Gudjonsson, Johann E. Kjems, Jorgen Kristensen, Lasse S. Aarhus Univ Dept Mol Biol & Genet MBG Aarhus C Denmark Aarhus Univ Interdisciplinary Nanosci Ctr iNANO Aarhus C Denmark Univ Michigan Med Sch Dept Dermatol Ann Arbor MI USA Univ Michigan Med Sch Dept Computat Med & Bioinformat Ann Arbor MI USA Univ Michigan Sch Publ Hlth Dept Biostat Ann Arbor MI 48109 USA Univ Hosp Schleswig Holstein Dept Dermatol Venereol & Allergy Kiel Germany Vejle Hosp Dept Clin Pathol Vejle Denmark Aarhus Univ Dept Biomed Fac Hlth DK-8000 Aarhus C Denmark

Atopic dermatitis (AD) and psoriasis are two common chronic inflammatory skin diseases that are associated with various comorbidities. Circular rna (circrna) constitutes a major class of non-coding rnas that have been implicated in many human diseases, although their potential involvement in inflammatory skin diseases remains elusive. Here, we compare and contrast the circrna expression landscapes in paired lesional and non-lesional skin from psoriasis and AD patients relative to skin from unaffected individuals using high-depth rna-seq data. Circrnas and their cognate linear transcripts were quantified using the circrna detection algorithm, CIRI2, and in situ hybridization and Sanger sequencing was used for validation purposes. We identified 39,286 circrnas among all samples and found that psoriasis and AD lesional skin could be distinguished from non-lesional and healthy skin based on circrna expression landscapes. In general, circrnas were less abundant in lesional relative to non-lesional and healthy skin. Differential expression analyses revealed many significantly downregulated circrnas, mainly in psoriasis lesional skin, and a strong correlation between psoriasis and AD-related circrna expression changes was observed. Two individual circrnas, ciRS-7 (also known as CDR1as) and circZRANB1, were specifically dysregulated in psoriasis and show promise as biomarkers for discriminating AD from psoriasis. In conclusion, the circrna transcriptomes of psoriasis and AD share expression features, including a global downregulation relative to healthy skin, but this is most pronounced in psoriasis, and only psoriasis is characterized by several circrnas being dysregulated independently of their cognate linear transcripts. Finally, specific circrnas could potentially be used to distinguish AD from psoriasis.

关键词： atopic dermatitis circular rna ciRS-7 next-generation sequencing non-coding rna psoriasis

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The non-coding epitranscriptome in cancer

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BRIEFINGS IN FUNCTIONAL GENOMICS 2021年第2期20卷 94-105页

作者： Miano, Valentina Codino, Azzurra Pandolfini, Luca Barbieri, Isaia Univ Cambridge RNA Modificat Blood Canc Cambridge England Ist Italiano Tecnol Dev Neurobiol RNA Genoa Italy Univ Cambridge Gurdon Inst Cambridge England Ist Italiano Tecnol Genoa Field Dev Neurobiol RNA Genoa Italy Univ Cambridge Dept Pathol Cambridge England

Post-synthesis modification of biomolecules is an efficient way of regulating and optimizing their functions. The human epitranscriptome includes a variety of more than 100 modifications known to exist in all rna subtypes. Modifications of non-coding rnas are particularly interesting since they can directly affect their structure, stability, interaction and function. Indeed, non-coding rnas such as trna and rrna are the most modified rna species in eukaryotic cells. In the last 20 years, new functions of non-coding rnas have been discovered and their involvement in human disease, including cancer, became clear. In this review, we will present the evidence connecting modifications of different non-coding rna subtypes and their role in cancer.

关键词： non-coding rna epitranscriptomics rna epigenetics cancer rna modifications rna methylation

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