{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T21:35:07Z","timestamp":1787866507236,"version":"build-2784847793"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:00:00Z","timestamp":1776470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Soci\u00e9t\u00e9 Francophone de N\u00e9phrologie Dialyse et Transplantation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The human genome produces a large repertoire of non-coding RNAs (ncRNAs) with important regulatory roles in development, physiology, and most of diseases. Among these, long non-coding RNAs (lncRNAs) have emerged as key modulators of gene expression, chromatin organization, and cellular homeostasis, despite displaying remarkably low primary-sequence conservation across species. This apparent evolutionary paradox questions the limitations of predicting biological function based on conservation, particularly across different biological domains. Here, we examine current evidence on lncRNA evolution, with a focus on their roles in metabolic regulation compared with neurobiological processes. We hypothesize that lncRNAs involved in ancient and conserved pathways such as metabolism may be under stronger evolutionary constraint than those associated with higher-order, species-specific traits, although available data support a more nuanced interpretation. Functional importance often correlates poorly with linear sequence conservation and instead appears to depend on higher-level features, including RNA secondary or tertiary structure, genomic context, regulatory architecture, and interactions with conserved molecular partners. We propose a systematic comparative framework to empirically assess conservation among metabolism- and neuro-associated lncRNAs using phylogenetic, syntenic, structural, and expression-based metrics. Finally, we discuss the therapeutic implications of lncRNA biology, highlighting how a deeper understanding of their evolutionary and mechanistic properties may inform the development of more precise and effective RNA-targeting strategies. Together, these insights underscore the non-coding transcriptome as a critical frontier for both fundamental biology and precision medicine.<\/jats:p>","DOI":"10.3390\/genes17040484","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T09:37:42Z","timestamp":1776677862000},"page":"484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Could Metabolism-Related Long Non-Coding RNAs Be More Conserved than Their Brain-Related Counterparts?"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7636-8480","authenticated-orcid":false,"given":"Laurent","family":"Metzinger","sequence":"first","affiliation":[{"name":"HEMATIM UR 4666, C.U.R.S, University of Picardie Jules Verne, CEDEX 1, 80025 Amiens, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1718-5083","authenticated-orcid":false,"given":"Val\u00e9rie","family":"Metzinger-Le Meuth","sequence":"additional","affiliation":[{"name":"HEMATIM UR 4666, C.U.R.S, University of Picardie Jules Verne, CEDEX 1, 80025 Amiens, France"},{"name":"INSERM UMRS 1148, Laboratory for Vascular Translational Science (LVTS), UFR SMBH, University Sorbonne Paris Nord, 93000 Bobigny, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1126\/science.1112014","article-title":"The transcriptional landscape of the mammalian genome","volume":"309","author":"Carninci","year":"2005","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1126\/science.1068597","article-title":"Large-scale transcriptional activity in chromosomes 21 and 22","volume":"296","author":"Kapranov","year":"2002","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/nature21374","article-title":"An atlas of human long non-coding RNAs with accurate 5\u2032 ends","volume":"543","author":"Hon","year":"2017","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/s41580-022-00566-8","article-title":"Long non-coding RNAs: Definitions, functions, challenges and recommendations","volume":"24","author":"Mattick","year":"2023","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nature04733","article-title":"Polycomb complexes repress developmental regulators in murine embryonic stem cells","volume":"441","author":"Boyer","year":"2006","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.cell.2005.02.016","article-title":"A Rae1-containing ribonucleoprotein complex is required for mitotic spindle assembly","volume":"121","author":"Blower","year":"2005","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/jcb.10326","article-title":"The 5\u2032-untranslated RNA of the human dhfr minor transcript alters transcription pre-initiation complex assembly at the major (core) promoter","volume":"88","author":"Blume","year":"2003","journal-title":"J. Cell. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1101\/gr.254219.119","article-title":"Functional annotation of human long noncoding RNAs via molecular phenotyping","volume":"30","author":"Ramilowski","year":"2020","journal-title":"Genome Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Fourdinier, O., Glorieux, G., Brigant, B., Diouf, M., Pletinck, A., Vanholder, R., Choukroun, G., Verbeke, F., Massy, Z.A., and Meuth, V.M.-L. (2021). Syndecan-1 and Free Indoxyl Sulfate Levels Are Associated with miR-126 in Chronic Kidney Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910549"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ncrna.2025.04.009","article-title":"Uremic toxins levels are associated with miR-223 in chronic kidney disease-associated anemia","volume":"13","author":"Brisot","year":"2025","journal-title":"Non-Coding RNA Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e202302002","DOI":"10.26508\/lsa.202302002","article-title":"Multidimensional conservation analysis decodes the expression of conserved long noncoding RNAs","volume":"6","author":"Zhou","year":"2023","journal-title":"Life Sci. Alliance"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s00335-021-09924-x","article-title":"Getting to the bottom of lncRNA mechanism: Structure\u2013function relationships","volume":"33","author":"Sanbonmatsu","year":"2022","journal-title":"Mamm. Genome. Off. J. Int. Mamm. Genome. Soc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1093\/nargab\/lqz002","article-title":"Conserved regions in long non-coding RNAs contain abundant translation and protein\u2013RNA interaction signatures","volume":"1","year":"2019","journal-title":"NAR Genom. Bioinform."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e2411918121","DOI":"10.1073\/pnas.2411918121","article-title":"Accelerated cell-type-specific regulatory evolution of the human brain","volume":"121","author":"Joshy","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhang, T.-N., Wang, W., Yang, N., Huang, X.-M., and Liu, C.-F. (2020). Regulation of Glucose and Lipid Metabolism by Long Non-coding RNAs: Facts and Research Progress. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00457"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.bbrc.2015.11.048","article-title":"Upregulation of lncRNA MEG3 promotes hepatic insulin resistance via increasing FoxO1 expression","volume":"469","author":"Zhu","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"RP96988","DOI":"10.7554\/eLife.96988.4","article-title":"LncRNA Snhg3 aggravates hepatic steatosis via PPAR\u03b3 signaling","volume":"13","author":"Xie","year":"2024","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7597","DOI":"10.1007\/s11033-023-08527-w","article-title":"Dyslipidemia initiates keratinocytes proliferation through upregulation of lncRNA NEAT in psoriasis patients","volume":"50","author":"Mostafa","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"105527","DOI":"10.1016\/j.biosystems.2025.105527","article-title":"An account of a century of ATP research","volume":"256","author":"Nath","year":"2025","journal-title":"Biosystems"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1261\/rna.079210.122","article-title":"The mutual interaction of glycolytic enzymes and RNA in post-transcriptional regulation","volume":"28","author":"Wegener","year":"2022","journal-title":"RNA"},{"key":"ref_21","first-page":"65","article-title":"Coincidence, coevolution, or causation? DNA content, cell size, and the C-value enigma","volume":"76","author":"Gregory","year":"2001","journal-title":"Biol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mirza, A.H., Kaur, S., Brorsson, C.A., and Pociot, F. (2014). Effects of GWAS-associated genetic variants on lncRNAs within IBD and T1D candidate Loci. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105723"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/nrg.2016.85","article-title":"Evolution to the rescue: Using comparative genomics to understand long non-coding RNAs","volume":"17","author":"Ulitsky","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"101878","DOI":"10.1016\/j.arr.2023.101878","article-title":"lncRNA NEAT1: Key player in neurodegenerative diseases","volume":"86","author":"Li","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1821252","DOI":"10.1155\/2024\/1821252","article-title":"Targeting lncRNA MALAT1: A Promising Approach to Overcome Metabolic Syndrome","volume":"2024","author":"Aihemaiti","year":"2024","journal-title":"Int. J. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/nature12943","article-title":"The evolution of lncRNA repertoires and expression patterns in tetrapods","volume":"505","author":"Necsulea","year":"2014","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1093\/bioinformatics\/bty966","article-title":"PhastWeb: A web interface for evolutionary conservation scoring of multiple sequence alignments using phastCons and phyloP","volume":"35","author":"Ramani","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Davydov, E.V., Goode, D.L., Sirota, M., Cooper, G.M., Sidow, A., and Batzoglou, S. (2010). Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput. Biol., 6.","DOI":"10.1371\/journal.pcbi.1001025"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Park, K.-J., Yoon, Y.A., and Park, J.-H. (2023). Evaluation of Liftover Tools for the Conversion of Genome Reference Consortium Human Build 37 to Build 38 Using ClinVar Variants. Genes, 14.","DOI":"10.3390\/genes14101875"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/978-1-4939-9173-0_10","article-title":"Coding Exon-Structure Aware Realigner (CESAR): Utilizing Genome Alignments for Comparative Gene Annotation","volume":"1962","author":"Sharma","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"bav096","DOI":"10.1093\/database\/bav096","article-title":"Ensembl comparative genomics resources","volume":"2016","author":"Herrero","year":"2016","journal-title":"Database"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e49","DOI":"10.1093\/nar\/gkr1293","article-title":"MCScanX: A toolkit for detection and evolutionary analysis of gene synteny and collinearity","volume":"40","author":"Wang","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1101\/gr.5650707","article-title":"Structured RNAs in the ENCODE selected regions of the human genome","volume":"17","author":"Washietl","year":"2007","journal-title":"Genome Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Rivas, E. (2023). RNA covariation at helix-level resolution for the identification of evolutionarily conserved RNA structure. PLoS Comput. Biol., 19.","DOI":"10.1101\/2023.04.14.536965"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1093\/bib\/bbx108","article-title":"MAFFT online service: Multiple sequence alignment, interactive sequence choice and visualization","volume":"20","author":"Katoh","year":"2019","journal-title":"Brief. Bioinform."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-0716-1036-7_1","article-title":"The Clustal Omega Multiple Alignment Package","volume":"2231","author":"Sievers","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.18632\/aging.202648","article-title":"Ageing transcriptome meta-analysis reveals similarities and differences between key mammalian tissues","volume":"13","author":"Palmer","year":"2021","journal-title":"Aging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"107083","DOI":"10.1016\/j.phrs.2024.107083","article-title":"Metabolic disorders affecting the liver and heart: Therapeutic efficacy of miRNA-based therapies?","volume":"201","author":"Carlini","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Moreno, J.A., Hamza, E., Guerrero-Hue, M., Rayego-Mateos, S., Garc\u00eda-Caballero, C., Vallejo-Mudarra, M., Metzinger, L., and Meuth, V.M.-L. (2021). Non-Coding RNAs in Kidney Diseases: The Long and Short of Them. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22116077"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s12033-022-00567-0","article-title":"A Review on the Mechanism and Applications of CRISPR\/Cas9\/Cas12\/Cas13\/Cas14 Proteins Utilized for Genome Engineering","volume":"65","author":"Hillary","year":"2023","journal-title":"Mol. Biotechnol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/484\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T10:01:58Z","timestamp":1776679318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/484"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,18]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["genes17040484"],"URL":"https:\/\/doi.org\/10.3390\/genes17040484","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,18]]}}}