{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T05:11:23Z","timestamp":1788757883022,"version":"build-2803163510"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    Non-coding RNAs (ncRNAs) are central regulators of epigenomic states, orchestrating chromatin modifications, gene silencing, and nuclear architecture through recruitment of chromatin-modifying complexes. Long noncoding RNAs (lncRNAs) such as XIST, HOTAIR, and MALAT1 exemplify these regulatory roles. Despite their importance, quantitative computational frameworks for linking ncRNA sequence composition to temporal regulatory behaviour remain limited. We introduce a frequency-domain control theory framework modelling RNA sequences as cascaded feedback systems, extending a previously established second-order negative feedback model developed for hormonal endocrine axis dynamics (1,2). This paper constitutes the molecular layer beneath that endocrine framework: where the companion paper characterises the cortisol\u2013HPA axis at the hormonal timescale (\n                    <jats:italic>\u03c4 \u2248<\/jats:italic>\n                    130\n                    <jats:italic>\u00a0min<\/jats:italic>\n                    , ultradian period\n                    <jats:italic>\u223c<\/jats:italic>\n                    90\n                    <jats:italic>\u00a0min<\/jats:italic>\n                    ), the present work resolves the finer-grained tier of lncRNA-mediated chromatin responses (8\u201324 min) that constitutes the molecular machinery through which hormonal signals are transduced into epigenetic change. Together, the two frameworks delineate a two-tier frequency hierarchy: the hormonal cascade sets the input signal timescale, and ncRNA sequence composition determines whether the downstream chromatin response is bandwidth-matched to follow it. As a proof-of-concept demonstration using one representative miRNA and one lncRNA sequence, analysis reveals that RNA length and topology encode low-pass temporal filtering properties, with ncRNAs exhibiting slower cutoff frequencies and stronger noise attenuation than short miRNAs. The parameter mapping from sequence composition to control-theoretic parameters is treated as an abstract mathematical heuristic rather than a literal physical law, and the framework is intended to generate experimentally testable hypotheses rather than quantitative physiological predictions. Mixed miRNA\u2013ncRNA cascades show extreme phase accumulation at the stability boundary, a necessary but not sufficient condition for bistable or oscillatory epigenetic regulation. ncRNA sequence composition systematically encodes temporal response characteristics relevant to epigenetic regulation, providing a theoretical basis for predictive modelling of chromatin dynamics and RNA-mediated control systems.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2026.1900294","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T04:22:51Z","timestamp":1788754971000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From sequence to timescale: a frequency-domain control-theoretic framework linking ncRNA sequence composition to epigenetic regulatory timescales"],"prefix":"10.3389","volume":"17","author":[{"given":"Massoud","family":"Boroujerdi","sequence":"first","affiliation":[{"name":"Independent Researcher","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3414\/ME12-01-0076","article-title":"A negative feedback model for a mechanism based description of longitudinal observations","volume":"52","author":"Boroujerdi","year":"2013","journal-title":"Methods Inf Med"},{"key":"B2","volume-title":"A Generic Model for Dynamics Simulation: An R Shiny App for Type One Diabetes Mellitus","author":"Boroujerdi","year":"2024"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90520-M","article-title":"The human XIST gene: Analysis of a 17-kb RNA molecule that is expressed only from the inactive X chromosome and contains conserved repetitive domains","volume":"71","author":"Brown","year":"1992","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.05.022","article-title":"Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs","volume":"129","author":"Rinn","year":"2007","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.08.011","article-title":"The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation","volume":"39","author":"Tripathi","year":"2010","journal-title":"Mol Cell"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/science.1099962","article-title":"Oscillations in NF-\u03baB signaling control the dynamics of gene expression","volume":"306","author":"Nelson","year":"2004","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508658103","article-title":"Real-time imaging of the somite segmentation clock: Revelation of unstable oscillators in the individual presomitic mesoderm cells","volume":"103","author":"Masamizu","year":"2006","journal-title":"Proc Natl Acad Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/ng1293","article-title":"Dynamics of the p53-Mdm2 feedback loop in individual cells","volume":"36","author":"Lahav","year":"2004","journal-title":"Nat Genet"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.05.009","article-title":"Regulatory interactions between RNA and polycomb repressive complex 2","volume":"55","author":"Cifuentes-Rojas","year":"2014","journal-title":"Mol Cell"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1126\/science.1237973","article-title":"The xist lncRNA exploits three-dimensional genome architecture to spread across the x chromosome","volume":"341","author":"Engreitz","year":"2013","journal-title":"Science"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.01.026","article-title":"An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles","volume":"33","author":"Clemson","year":"2009","journal-title":"Mol Cell"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.251","article-title":"Alternative 3\u2019-end processing of long noncoding RNA initiates construction of nuclear paraspeckles","volume":"31","author":"Naganuma","year":"2012","journal-title":"EMBO J"},{"key":"B13","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1016\/j.cell.2013.07.011","article-title":"Mechanisms and functions of ATP-dependent chromatin-remodeling enzymes","volume":"154","author":"Narlikar","year":"2013","journal-title":"Cell"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.26","article-title":"Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes","volume":"18","author":"Clapier","year":"2017","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1126\/science.1198817","article-title":"Mammalian genes are transcribed with widely different bursting kinetics","volume":"332","author":"Suter","year":"2011","journal-title":"Science"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0836-1","article-title":"Genomic encoding of transcriptional burst kinetics","volume":"565","author":"Larsson","year":"2019","journal-title":"Nature"},{"key":"B17","volume-title":"Biomolecular Feedback Systems","author":"Del Vecchio","year":"2014"},{"key":"B18","volume-title":"Modern Control Engineering","author":"Ogata","year":"2010"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/science.1258699","article-title":"Epigenetic inheritance uncoupled from sequence-specific recruitment","volume":"348","author":"Ragunathan","year":"2015","journal-title":"Science"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1141","article-title":"miRBase: From microRNA sequences to function","volume":"47","author":"Kozomara","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1252","article-title":"NONCODE 2016: An informative and valuable data source of long non-coding RNAs","volume":"44","author":"Zhao","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"B22","unstructured":"NONCODE: An integrated knowledge database of non-coding RNAs\n          \n          2023"},{"key":"B23","volume-title":"Understanding bode plots","year":""},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005146","article-title":"DREISS: Using state-space models to infer the dynamics of gene expression driven by external and internal regulatory networks","volume":"12","author":"Yang","year":"2016","journal-title":"PloS Comput Biol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1093\/dnares\/dsn030","article-title":"Database for mRNA half-life of 19\u2013977 genes obtained by DNA microarray analysis of pluripotent and differentiating mouse embryonic stem cells","volume":"16","author":"Sharova","year":"2009","journal-title":"DNA Res"},{"key":"B26","doi-asserted-by":"publisher","first-page":"6821","DOI":"10.1038\/s41467-024-50402-0","article-title":"The temporal dynamics of lncRNA Firre-mediated epigenetic and transcriptional regulation","volume":"15","author":"Lewandowski","year":"2024","journal-title":"Nat Commun"},{"key":"B27","doi-asserted-by":"publisher","first-page":"9263","DOI":"10.1038\/s41467-024-53539-0","article-title":"Optogenetic dissection of transcriptional repression in a multicellular organism","volume":"15","author":"Zhao","year":"2024","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","first-page":"dev204403","DOI":"10.1242\/dev.204403","article-title":"Optogenetic control of cAMP oscillations reveals frequencyselective transcription factor dynamics in dictyostelium","volume":"152","author":"Yamashita","year":"2025","journal-title":"Development"},{"key":"B29","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.molcel.2005.02.032","article-title":"The speed of RNA transcription and metabolite binding kinetics operate an FMN riboswitch","volume":"18","author":"Wickiser","year":"2005","journal-title":"Mol Cell"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.2210\/pdb2gis\/pdb","article-title":"Structure of the s-adenosylmethionine riboswitch regulatory mRNA element","volume":"441","author":"Montange","year":"2006","journal-title":"Nature"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2006.06.010","article-title":"Folding of the adenine riboswitch","volume":"13","author":"Lemay","year":"2006","journal-title":"Chem Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.212628899","article-title":"An mRNA structure that controls gene expression by binding FMN","volume":"99","author":"Winkler","year":"2002","journal-title":"Proc Natl Acad Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1563","article-title":"Cocrystal structure of a class I PreQ1 riboswitch","volume":"16","author":"Klein","year":"2009","journal-title":"Nat Struct Mol Biol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.13051","article-title":"A continuum model of transcriptional bursting","volume":"5","author":"Corrigan","year":"2016","journal-title":"eLife"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12248","article-title":"A single-molecule view of transcription reveals convoys of RNA polymerases and multi-scale bursting","volume":"7","author":"Tantale","year":"2016","journal-title":"Nat Commun"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aaz6699","article-title":"Genome-wide kinetic properties of transcriptional bursting in mouse embryonic stem cells","volume":"6","author":"Ito","year":"2020","journal-title":"Sci Adv"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164860","article-title":"Pulsatile stimulation determines timing and specificity of NF-\u03bab-dependent transcription","volume":"324","author":"Ashall","year":"2009","journal-title":"Science"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/ng1372","article-title":"Instability of Hes7 protein is crucial for the somite segmentation clock","volume":"36","author":"Hirata","year":"2004","journal-title":"Nat Genet"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.64898\/2026.01.03.697472","article-title":"Impact of competition between precursor and mature microRNAs on stochastic gene expression","author":"Bhat","year":"2026","journal-title":"bioRxiv"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2026.153561","article-title":"Beyond the obvious: Exploring the underappreciated dynamics and contextspecific functions of lncRNAs","volume":"811","author":"Eladl","year":"2026","journal-title":"Biochem Biophys Res Commun"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2026.153673","article-title":"Epitranscriptomic RNA modifications in human disease: Cooperative networks, molecular mechanisms, and therapeutic opportunities","volume":"815","author":"Eladl","year":"2026","journal-title":"Biochem Biophys Res Commun"},{"key":"B42","doi-asserted-by":"publisher","first-page":"20519","DOI":"10.1038\/s41598-025-20519-3","article-title":"In-cell NMR spectroscopy of unmodified RNA in living human cells enabled by RNase inhibitor cocktail","volume":"15","author":"Oshima","year":"2025","journal-title":"Sci Rep"},{"key":"B43","doi-asserted-by":"publisher","first-page":"102374","DOI":"10.1016\/j.sbi.2022.102374","article-title":"In-cell NMR spectroscopy: Recent methodological advances and applications in structural biology","volume":"74","author":"LuChinat","year":"2025","journal-title":"Magn Reson Med"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1900294\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T04:22:53Z","timestamp":1788754973000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1900294\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,7]]},"references-count":43,"alternative-id":["10.3389\/fendo.2026.1900294"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1900294","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,7]]},"article-number":"1900294"}}