{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T12:29:41Z","timestamp":1777897781707,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre","award":["2017\/26\/E\/NZ5\/00851"],"award-info":[{"award-number":["2017\/26\/E\/NZ5\/00851"]}]},{"name":"National Science Centre","award":["2020\/39\/D\/NZ5\/02720"],"award-info":[{"award-number":["2020\/39\/D\/NZ5\/02720"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Correlation of genes within tissues has attracted much attention. In contrast, genes that are INDependent In Expression (INDIE) remain poorly understood, even though they may represent tissue admixtures, reflect new regulatory mechanisms, either transcriptional or post-transcriptional, and contribute to biomarkers or machine learning algorithms. We hypothesised that INDIE genes can be found, may remain uncorrelated across tissues, and replicate within tissues in external datasets. Methods: Biweight midcorrelation was calculated for each gene against all other genes with sufficiently high expression in the given tissue from the GTEx dataset v8, along with the means of absolute values of obtained correlation coefficients. The threshold for gene designation as INDIE was both absolute (r) and relative (Z-score), while the threshold for external validation in the whole blood (four datasets) and the ileum (two datasets) was relative. Results: Only one gene, RPL13P12, was INDIE in all the analysed GTEx tissues, but it did not replicate in the external datasets. In contrast, HIST1H2AD and TMEM176B were not only INDIE in GTEx whole blood but also replicated in all four external datasets, despite their heterogeneity. Moreover, ACAT2 replicated in both external ileal datasets. The haemoglobin gene HBB belonged to most widespread INDIE genes in various GTEx tissues and was validated in an external ileal dataset, pointing towards the importance of tissue heterogeneity in bulk samples. Conclusions: A set of genes exhibiting independent expression patterns across various tissues of GTEx was described. Results for each tissue are made available. Even though many findings can be explained by tissue heterogeneity, some results point towards interesting mechanisms of gene expression regulation.<\/jats:p>","DOI":"10.3390\/genes16091067","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T12:04:55Z","timestamp":1757505895000},"page":"1067","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exceptions to Broad Tissue-Specific Transcriptomic Interdependence: Searching for Independence in Expression of Genes"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2344-9471","authenticated-orcid":false,"given":"Miko\u0142aj","family":"Danielewski","sequence":"first","affiliation":[{"name":"Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Szpitalna 27\/33, 60-572 Poznan, Poland"},{"name":"Doctoral School, Poznan University of Medical Sciences, Bukowska 70, 60-812 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5813-5707","authenticated-orcid":false,"given":"Jaros\u0142aw","family":"Walkowiak","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Szpitalna 27\/33, 60-572 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0629-2991","authenticated-orcid":false,"given":"Karolina","family":"Wielgus","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Szpitalna 27\/33, 60-572 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0953-2188","authenticated-orcid":false,"given":"Jan Krzysztof","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Szpitalna 27\/33, 60-572 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","first-page":"575","article-title":"Gene Co-Expression Analysis for Functional Classification and Gene\u2013Disease Predictions","volume":"19","author":"Franke","year":"2018","journal-title":"Brief. Bioinform."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1145\/45072.45074","article-title":"Data Compression","volume":"19","author":"Lelewer","year":"1987","journal-title":"ACM Comput. Surv."},{"key":"ref_3","first-page":"20110534","article-title":"Independent Component Analysis: Recent Advances","volume":"371","year":"2013","journal-title":"Philos. Trans. R. Soc. A Math. Phys. Eng. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1126\/science.1255905","article-title":"Correlated Gene Expression Supports Synchronous Activity in Brain Networks","volume":"348","author":"Richiardi","year":"2015","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"i124","DOI":"10.1093\/bioinformatics\/bty293","article-title":"Scalable Preprocessing for Sparse scRNA-Seq Data Exploiting Prior Knowledge","volume":"34","author":"Mukherjee","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s40537-024-01051-z","article-title":"Correlation-Based Feature Selection of Single Cell Transcriptomics Data from Multiple Sources","volume":"12","author":"Malkov","year":"2025","journal-title":"J. Big Data"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1038\/s41586-024-08518-2","article-title":"Transcriptomic Neuron Types Vary Topographically in Function and Morphology","volume":"638","author":"Shainer","year":"2025","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1093\/ecco-jcc\/jjac033","article-title":"Characterisation of the Circulating Transcriptomic Landscape in Inflammatory Bowel Disease Provides Evidence for Dysregulation of Multiple Transcription Factors Including NFE2, SPI1, CEBPB, and IRF2","volume":"16","author":"Nowak","year":"2022","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"GTEx Consortium (2020). The GTEx Consortium Atlas of Genetic Regulatory Effects across Human Tissues. Science, 369, 1318\u20131330.","DOI":"10.1126\/science.aaz1776"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Langfelder, P., and Horvath, S. (2008). WGCNA: An R Package for Weighted Correlation Network Analysis. BMC Bioinform., 9.","DOI":"10.1186\/1471-2105-9-559"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1213\/ANE.0000000000002864","article-title":"Correlation Coefficients: Appropriate Use and Interpretation","volume":"126","author":"Schober","year":"2018","journal-title":"Anesth. Analg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e508","DOI":"10.1016\/S2666-5247(21)00146-4","article-title":"Blood Transcriptional Biomarkers of Acute Viral Infection for Detection of Pre-Symptomatic SARS-CoV-2 Infection: A Nested, Case-Control Diagnostic Accuracy Study","volume":"2","author":"Gupta","year":"2021","journal-title":"Lancet Microbe"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10434","DOI":"10.1038\/s41467-024-54764-3","article-title":"SARS-CoV-2 Human Challenge Reveals Biomarkers That Discriminate Early and Late Phases of Respiratory Viral Infections","volume":"15","author":"Rosenheim","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1038\/s41467-018-04365-8","article-title":"IBD Risk Loci Are Enriched in Multigenic Regulatory Modules Encompassing Putative Causative Genes","volume":"9","author":"Momozawa","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1172\/JCI75436","article-title":"Pediatric Crohn Disease Patients Exhibit Specific Ileal Transcriptome and Microbiome Signature","volume":"124","author":"Haberman","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/pro.4218","article-title":"PANTHER: Making Genome-Scale Phylogenetics Accessible to All","volume":"31","author":"Thomas","year":"2022","journal-title":"Protein Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4578","DOI":"10.1093\/bioinformatics\/btab503","article-title":"UCSC Cell Browser: Visualize Your Single-Cell Data","volume":"37","author":"Speir","year":"2021","journal-title":"Bioinformatics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.cels.2015.10.001","article-title":"NDEx, the Network Data Exchange","volume":"1","author":"Pratt","year":"2015","journal-title":"Cell Syst."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Pillich, R.T., Chen, J., Churas, C., Fong, D., Gyori, B.M., Ideker, T., Karis, K., Liu, S.N., Ono, K., and Pico, A. (2023). NDEx IQuery: A Multi-Method Network Gene Set Analysis Leveraging the Network Data Exchange. Bioinformatics, 39.","DOI":"10.1093\/bioinformatics\/btad118"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e258","DOI":"10.1002\/cpz1.258","article-title":"NDEx: Accessing Network Models and Streamlining Network Biology Workflows","volume":"1","author":"Pillich","year":"2021","journal-title":"Curr. Protoc."},{"key":"ref_21","unstructured":"Wu, C.H., Arighi, C.N., and Ross, K.E. (2017). NDEx: A Community Resource for Sharing and Publishing of Biological Networks. Protein Bioinformatics: From Protein Modifications and Networks to Proteomics, Springer."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e58","DOI":"10.1158\/0008-5472.CAN-17-0606","article-title":"NDEx 2.0: A Clearinghouse for Research on Cancer Pathways","volume":"77","author":"Pratt","year":"2017","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1152\/physiolgenomics.00040.2001","article-title":"A Compendium of Gene Expression in Normal Human Tissues","volume":"7","author":"Hsiao","year":"2001","journal-title":"Physiol. Genom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00726-025-03447-4","article-title":"Unveiling the Tissue-Specific Landscape of Nuclear-Encoded Mitochondrial Genes Involved in Amino Acid Metabolism in Buffalo","volume":"57","author":"Sadeesh","year":"2025","journal-title":"Amino Acids"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1038\/ejhg.2013.293","article-title":"Population-Level Expression Variability of Mitochondrial DNA-Encoded Genes in Humans","volume":"22","author":"Wang","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"vdad104","DOI":"10.1093\/noajnl\/vdad104","article-title":"Longitudinal Analysis of Serum-Derived Extracellular Vesicle RNA to Monitor Dacomitinib Treatment Response in EGFR-Amplified Recurrent Glioblastoma Patients","volume":"5","author":"Yekula","year":"2023","journal-title":"Neuro-Oncol. Adv."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1186\/s12943-023-01875-y","article-title":"A Liquid Biopsy Signature of Circulating Extracellular Vesicles-Derived RNAs Predicts Response to First Line Chemotherapy in Patients with Metastatic Colorectal Cancer","volume":"22","author":"Yang","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1261\/rna.2658311","article-title":"Pseudogenes: Pseudo-Functional or Key Regulators in Health and Disease?","volume":"17","author":"Pink","year":"2011","journal-title":"RNA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1101\/gr.176115.114","article-title":"A Novel Role for the Pol I Transcription Factor UBTF in Maintaining Genome Stability through the Regulation of Highly Transcribed Pol II Genes","volume":"25","author":"Sanij","year":"2015","journal-title":"Genome Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.jiph.2023.01.015","article-title":"Evaluation of Differentially Expressed Genes during Replication Using Gene Expression Landscape of Monkeypox-Infected MK2 Cells: A Bioinformatics and Systems Biology Approach to Understanding the Genomic Pattern of Viral Replication","volume":"16","author":"Chakraborty","year":"2023","journal-title":"J. Infect. Public Health"},{"key":"ref_31","unstructured":"Hashimoto, A. (2017). Next Generation Sequencing to Identify New Genetic Causes of Familial Craniosynostosis. [Doctoral Dissertation, University of Oxford]. Available online: https:\/\/ora.ox.ac.uk\/objects\/uuid:e72022d1-d77d-4d0f-8419-950599bd1b2c."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Victoria, S., Castro, A., Pittini, A., Olivera, D., Russo, S., Cebrian, I., Mombru, A.W., Osinaga, E., Pardo, H., and Segovia, M. (2024). Formulating a TMEM176B Blocker in Chitosan Nanoparticles Uncouples Its Paradoxical Roles in Innate and Adaptive Antitumoral Immunity. Int. J. Biol. Macromol., 279.","DOI":"10.1016\/j.ijbiomac.2024.135327"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Luo, X., Luo, B., Fei, L., Zhang, Q., Liang, X., Chen, Y., and Zhou, X. (2024). MS4A Superfamily Molecules in Tumors, Alzheimer\u2019s and Autoimmune Diseases. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1481494"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jiang, L., Yi, R., Chen, H., and Wu, S. (2025). Quercetin Alleviates Metabolic-Associated Fatty Liver Disease by Tuning Hepatic Lipid Metabolism, Oxidative Stress and Inflammation. Anim. Biotechnol., 36.","DOI":"10.1080\/10495398.2024.2442351"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1161\/HYPERTENSIONAHA.124.24277","article-title":"Identification of Novel Therapeutic Targets for Hypertension","volume":"82","author":"Zheng","year":"2025","journal-title":"Hypertension"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1002\/path.6400","article-title":"PI3 Expression Predicts Recurrence after Chemotherapy with DNA-damaging Drugs in Gastric Cancer","volume":"265","author":"Harada","year":"2025","journal-title":"J. Pathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/s41419-024-06666-x","article-title":"ACAT2 Suppresses the Ubiquitination of YAP1 to Enhance the Proliferation and Metastasis Ability of Gastric Cancer via the Upregulation of SETD7","volume":"15","author":"Zhang","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Latiano, A., Palmieri, O., Pastorelli, L., Vecchi, M., Pizarro, T.T., Bossa, F., Merla, G., Augello, B., Latiano, T., and Corritore, G. (2013). Associations between Genetic Polymorphisms in IL-33, IL1R1 and Risk for Inflammatory Bowel Disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062144"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"D\u00edaz-Jim\u00e9nez, D., N\u00fa\u00f1ez, L., De la Fuente, M., Dubois-Camacho, K., Sep\u00falveda, H., Montecino, M., Torres-Riquelme, A., Garc\u00eda-Gonz\u00e1lez, P., Chnaiderman, J., and Vossenkamper, A. (2017). A Functional IL1RL1 Variant Regulates Corticosteroid-Induced sST2 Expression in Ulcerative Colitis. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-10465-0"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1016\/j.chom.2021.06.019","article-title":"Multi-Omics Reveal Microbial Determinants Impacting Responses to Biologic Therapies in Inflammatory Bowel Disease","volume":"29","author":"Lee","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1097\/MIB.0000000000000179","article-title":"Two-Stage Genome-Wide Methylation Profiling in Childhood-Onset Crohn\u2019s Disease Implicates Epigenetic Alterations at the VMP1\/MIR21 and HLA Loci","volume":"20","author":"Adams","year":"2014","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1093\/ecco-jcc\/jjac119","article-title":"Systematic Review and Meta-Analysis of Peripheral Blood DNA Methylation Studies in Inflammatory Bowel Disease","volume":"17","author":"Joustra","year":"2023","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e2538","DOI":"10.1038\/cddis.2016.458","article-title":"Neuronal Hemoglobin Affects Dopaminergic Cells\u2019 Response to Stress","volume":"8","author":"Codrich","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Zheng, R., Yan, Y., Pu, J., and Zhang, B. (2022). Physiological and Pathological Functions of Neuronal Hemoglobin: A Key Underappreciated Protein in Parkinson\u2019s Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169088"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1002\/cne.22062","article-title":"Neurons Express Hemoglobin \u03b1- and \u03b2-Chains in Rat and Human Brains","volume":"515","author":"Richter","year":"2009","journal-title":"J. Comp. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"154726","DOI":"10.1016\/j.prp.2023.154726","article-title":"Screening and Identification of Potential Biomarkers for Pancreatic Cancer: An Integrated Bioinformatics Analysis","volume":"249","author":"Jafari","year":"2023","journal-title":"Pathol. Res. Pract."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Pelia, R., Venkateswaran, S., Matthews, J.D., Haberman, Y., Cutler, D.J., Hyams, J.S., Denson, L.A., and Kugathasan, S. (2021). Profiling Non-Coding RNA Levels with Clinical Classifiers in Pediatric Crohn\u2019s Disease. BMC Med. Genom., 14.","DOI":"10.1186\/s12920-021-01041-7"},{"key":"ref_48","unstructured":"Onwuegbuzie, A.J., and Daniel, L.G. (1999). Uses and Misuses of the Correlation Coefficient."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/9\/1067\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:43:12Z","timestamp":1760035392000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/9\/1067"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":48,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["genes16091067"],"URL":"https:\/\/doi.org\/10.3390\/genes16091067","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,10]]}}}