{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T11:27:29Z","timestamp":1781090849020,"version":"3.54.1"},"reference-count":55,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T00:00:00Z","timestamp":1572480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The Drosophila grainyhead (grh) and vertebrate Grainyhead-like (Grhl) transcription factors are among the most critical genes for epithelial development, maintenance and homeostasis, and are remarkably well conserved from fungi to humans. Mutations affecting grh\/Grhl function lead to a myriad of developmental and adult onset epithelial disease, such as aberrant skin barrier formation, facial\/palatal clefting, impaired neural tube closure, age-related hearing loss, ectodermal dysplasia, and importantly, cancers of epithelial origin. Recently, mutations in the family member GRHL3 have been shown to lead to both syndromic and non-syndromic facial and palatal clefting in humans, particularly the genetic disorder Van Der Woude Syndrome (VWS), as well as spina bifida, whereas mutations in mammalian Grhl2 lead to exencephaly and facial clefting. As transcription factors, Grhl proteins bind to and activate (or repress) a substantial number of target genes that regulate and drive a cascade of transcriptional networks. A multitude of large-scale datasets have been generated to explore the grh\/Grhl-dependent transcriptome, following ablation or mis-regulation of grh\/Grhl-function. Here, we have performed a meta-analysis of all 41 currently published grh and Grhl RNA-SEQ, and microarray datasets, in order to identify and characterise the transcriptional networks controlled by grh\/Grhl genes across disparate biological contexts. Moreover, we have also cross-referenced our results with published ChIP and ChIP-SEQ datasets, in order to determine which of the critical effector genes are likely to be direct grh\/Grhl targets, based on genomic occupancy by grh\/Grhl genes. Lastly, to interrogate the predictive strength of our approach, we experimentally validated the expression of the top 10 candidate grhl target genes in epithelial development, in a zebrafish model lacking grhl3, and found that orthologues of seven of these (cldn23, ppl, prom2, ocln, slc6a19, aldh1a3, and sod3) were significantly down-regulated at 48 hours post-fertilisation. Therefore, our study provides a strong predictive resource for the identification of putative grh\/grhl effector target genes.<\/jats:p>","DOI":"10.3390\/genes10110876","type":"journal-article","created":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T12:38:23Z","timestamp":1572525503000},"page":"876","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Meta-Analysis of Grainyhead-Like Dependent Transcriptional Networks: A Roadmap for Identifying Novel Conserved Genetic Pathways"],"prefix":"10.3390","volume":"10","author":[{"given":"Nishanthi","family":"Mathiyalagan","sequence":"first","affiliation":[{"name":"Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora 3086, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee B.","family":"Miles","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora 3086, VIC, Australia"},{"name":"School of Biological Sciences, Monash University, Clayton 3168, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Australian Craniofacial Unit, Women and Children\u2019s Hospital, Adelaide 5005, SA, Australia"},{"name":"Faculty of Health Sciences, University of Adelaide, Adelaide 5005, SA, Australia"},{"name":"Nanjing Medical University, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4447-8164","authenticated-orcid":false,"given":"Tomasz","family":"Wilanowski","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Grills","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora 3086, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart J.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Central Clinical School, Monash University, 99 Commercial Rd., Melbourne 3004, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8141-4069","authenticated-orcid":false,"given":"M. Cristina","family":"Keightley","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biomedical Sciences, La Trobe University, Bendigo 3552, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4761-9831","authenticated-orcid":false,"given":"Agata","family":"Charzynska","sequence":"additional","affiliation":[{"name":"Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St.02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Dabrowski","sequence":"additional","affiliation":[{"name":"Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St.02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5828-9992","authenticated-orcid":false,"given":"Sebastian","family":"Dworkin","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora 3086, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1101\/gad.5.9.1672","article-title":"Developmental function of Elf-1: An essential transcription factor during embryogenesis in Drosophila","volume":"5","author":"Bray","year":"1991","journal-title":"Genes Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1126\/science.1107511","article-title":"A homolog of Drosophila grainy head is essential for epidermal integrity in mice","volume":"308","author":"Ting","year":"2005","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"202","DOI":"10.4161\/org.7.3.18431","article-title":"The planar cell polarity pathway in vertebrate epidermal development, homeostasis and repair","volume":"7","author":"Dworkin","year":"2011","journal-title":"Organogenesis"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Pare, A., Kim, M., Juarez, M.T., Brody, S., and McGinnis, W. (2012). The functions of grainy head-like proteins in animals and fungi and the evolution of apical extracellular barriers. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0036254"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1038\/nm961","article-title":"Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3","volume":"9","author":"Ting","year":"2003","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1242\/dev.01641","article-title":"BMP4-dependent expression of Xenopus Grainyhead-like 1 is essential for epidermal differentiation","volume":"132","author":"Tao","year":"2005","journal-title":"Development"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17607","DOI":"10.1038\/s41598-017-17898-7","article-title":"Mis-expression of grainyhead-like transcription factors in zebrafish leads to defects in enveloping layer (EVL) integrity, cellular morphogenesis and axial extension","volume":"7","author":"Miles","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/B978-0-12-386499-4.00002-1","article-title":"Grainy head and its target genes in epithelial morphogenesis and wound healing","volume":"98","author":"Wang","year":"2012","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Mlacki, M., Darido, C., Jane, S.M., and Wilanowski, T. (2014). Loss of Grainy head-like 1 is associated with disruption of the epidermal barrier and squamous cell carcinoma of the skin. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089247"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.ydbio.2006.07.015","article-title":"The Grainyhead-like epithelial transactivator Get-1\/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4","volume":"299","author":"Yu","year":"2006","journal-title":"Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/s41419-018-0901-6","article-title":"Loss of GRHL3 leads to TARC\/CCL17-mediated keratinocyte proliferation in the epidermis","volume":"9","author":"Goldie","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.ydbio.2010.07.017","article-title":"Regional neural tube closure defined by the Grainy head-like transcription factors","volume":"345","author":"Rifat","year":"2010","journal-title":"Dev. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.ebiom.2015.04.012","article-title":"Fate specification of neural plate border by canonical wnt signaling and Grhl3 is crucial for neural tube closure","volume":"2","author":"Mochida","year":"2015","journal-title":"EBioMedicine"},{"key":"ref_14","first-page":"4218","article-title":"Overexpression of Grainyhead-like 3 causes spina bifida and interacts genetically with mutant alleles of Grhl2 and Vangl2 in mice","volume":"27","author":"Gustavsson","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1093\/hmg\/ddz010","article-title":"The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation","volume":"28","author":"Kousa","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1242\/dev.066522","article-title":"Midbrain-hindbrain boundary patterning and morphogenesis are regulated by diverse grainy head-like 2-dependent pathways","volume":"139","author":"Dworkin","year":"2012","journal-title":"Development"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.mod.2014.05.005","article-title":"Grainyhead-like 3 regulation of endothelin-1 in the pharyngeal endoderm is critical for growth and development of the craniofacial skeleton","volume":"133","author":"Dworkin","year":"2014","journal-title":"Mech. Dev."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Goldie, S.J., Arhatari, B.D., Anderson, P., Auden, A., Partridge, D.D., Jane, S.M., and Dworkin, S. (2016). Mice lacking the conserved transcription factor Grainyhead-like 3 (Grhl3) display increased apposition of the frontal and parietal bones during embryonic development. BMC Dev. Biol., 16.","DOI":"10.1186\/s12861-016-0136-7"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ajhg.2013.11.009","article-title":"Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development","volume":"94","author":"Leslie","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.ajhg.2016.02.013","article-title":"Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate","volume":"98","author":"Mangold","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1002\/humu.23214","article-title":"Rare deleterious variants in GRHL3 are associated with human spina bifida","volume":"38","author":"Lemay","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"22250","DOI":"10.1038\/srep22250","article-title":"Distinct expression patterns of causative genes responsible for hereditary progressive hearing loss in non-human primate cochlea","volume":"6","author":"Hosoya","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.1093\/hmg\/ddr234","article-title":"Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28","volume":"20","author":"Han","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1007\/s13277-013-1244-7","article-title":"Clinical implications of GRHL3 protein expression in breast cancer","volume":"35","author":"Xu","year":"2014","journal-title":"Tumour. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1007\/s12032-013-0714-5","article-title":"Expression and role of grainyhead-like 2 in gastric cancer","volume":"30","author":"Xiang","year":"2013","journal-title":"Med. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1093\/carcin\/bgw027","article-title":"Grainyhead-like 2 regulates epithelial plasticity and stemness in oral cancer cells","volume":"37","author":"Chen","year":"2016","journal-title":"Carcinogenesis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.gene.2016.04.045","article-title":"Association study between Van der Woude Syndrome causative gene GRHL3 and nonsyndromic cleft lip with or without cleft palate in a Chinese cohort","volume":"588","author":"Wang","year":"2016","journal-title":"Gene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.ajhg.2014.08.001","article-title":"Mutations in GRHL2 result in an autosomal-recessive ectodermal Dysplasia syndrome","volume":"95","author":"Petrof","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1093\/hmg\/ddr031","article-title":"Over-expression of Grhl2 causes spina bifida in the Axial defects mutant mouse","volume":"20","author":"Brouns","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.ccr.2011.10.014","article-title":"Targeting of the tumor suppressor GRHL3 by a miR-21-dependent proto-oncogenic network results in PTEN loss and tumorigenesis","volume":"20","author":"Darido","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9356","DOI":"10.1073\/pnas.1307589110","article-title":"Evidence for multiple roles for grainyheadlike 2 in the establishment and maintenance of human mucociliary airway epithelium","volume":"110","author":"Gao","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1242\/dev.00218","article-title":"Grainy head controls apical membrane growth and tube elongation in response to Branchless\/FGF signalling","volume":"130","author":"Hemphala","year":"2003","journal-title":"Development"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1126\/science.1107573","article-title":"An epidermal barrier wound repair pathway in Drosophila is mediated by grainy head","volume":"308","author":"Mace","year":"2005","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.ydbio.2008.06.026","article-title":"Grhl3 and Lmo4 play coordinate roles in epidermal migration","volume":"321","author":"Hislop","year":"2008","journal-title":"Dev. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1016\/j.jid.2016.02.806","article-title":"Two ancient gene families are critical for maintenance of the mammalian skin barrier in postnatal life","volume":"136","author":"Cangkrama","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.devcel.2010.06.008","article-title":"Epidermal wound repair is regulated by the planar cell polarity signaling pathway","volume":"19","author":"Caddy","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/emboj.2008.24","article-title":"Perturbed desmosomal cadherin expression in grainy head-like 1-null mice","volume":"27","author":"Wilanowski","year":"2008","journal-title":"EMBO J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ydbio.2007.04.026","article-title":"CREB activity modulates neural cell proliferation, midbrain-hindbrain organization and patterning in zebrafish","volume":"307","author":"Dworkin","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1534\/genetics.116.195685","article-title":"Stable binding of the conserved transcription factor grainy head to its target genes throughout drosophila melanogaster development","volume":"205","author":"Nevil","year":"2017","journal-title":"Genetics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1936","DOI":"10.1128\/MCB.22.6.1936-1946.2002","article-title":"Binding of the RING polycomb proteins to specific target genes in complex with the grainyhead-like family of developmental transcription factors","volume":"22","author":"Tuckfield","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1038\/emboj.2009.142","article-title":"The epidermal differentiation-associated Grainyhead gene Get1\/Grhl3 also regulates urothelial differentiation","volume":"28","author":"Yu","year":"2009","journal-title":"EMBO J."},{"key":"ref_42","first-page":"1192","article-title":"Grainyhead-like 2 downstream targets act to suppress epithelial-to-mesenchymal transition during neural tube closure","volume":"143","author":"Ray","year":"2016","journal-title":"Development"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ydbio.2018.09.002","article-title":"Lung morphogenesis is orchestrated through Grainyhead-like 2 (Grhl2) transcriptional programs","volume":"443","author":"Kersbergen","year":"2018","journal-title":"Dev. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Hopkin, A.S., Gordon, W., Klein, R.H., Espitia, F., Daily, K., Zeller, M., Baldi, P., and Andersen, B. (2012). GRHL3\/GET1 and trithorax group members collaborate to activate the epidermal progenitor differentiation program. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002829"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5205","DOI":"10.1172\/JCI77138","article-title":"A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia","volume":"124","author":"Gordon","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Xiang, X., Deng, Z., Zhuang, X., Ju, S., Mu, J., Jiang, H., Zhang, L., Yan, J., Miller, D., and Zhang, H.G. (2012). Grhl2 determines the epithelial phenotype of breast cancers and promotes tumor progression. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050781"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1158\/0008-5472.CAN-11-4038","article-title":"Suppression of the Epithelial-Mesenchymal Transition by Grainyhead-Like-2","volume":"72","author":"Cieply","year":"2012","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1158\/1541-7786.MCR-16-0050","article-title":"Grainyhead-like 2 reverses the metabolic changes induced by the oncogenic epithelial-mesenchymal transition: Effects on anoikis","volume":"14","author":"Farris","year":"2016","journal-title":"Mol. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"19943","DOI":"10.1038\/srep19943","article-title":"GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification","volume":"6","author":"Chung","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.1158\/0008-5472.CAN-16-1616","article-title":"Novel androgen receptor coregulator GRHL2 exerts both oncogenic and antimetastatic functions in prostate cancer","volume":"77","author":"Paltoglou","year":"2017","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.ydbio.2010.11.011","article-title":"The unique and cooperative roles of the Grainy head-like transcription factors in epidermal development reflect unexpected target gene specificity","volume":"349","author":"Boglev","year":"2011","journal-title":"Dev. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.ydbio.2011.02.027","article-title":"Grainyhead-like 2 regulates neural tube closure and adhesion molecule expression during neural fold fusion","volume":"353","author":"Pyrgaki","year":"2011","journal-title":"Dev. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1038\/ng1903","article-title":"Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6)","volume":"38","author":"Ingraham","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"pii: djv152","DOI":"10.1093\/jnci\/djv152","article-title":"Identification of a novel proto-oncogenic network in head and neck squamous cell carcinoma","volume":"107","author":"Georgy","year":"2015","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1073\/pnas.1016386108","article-title":"Phosphorylation of Grainy head by ERK is essential for wound-dependent regeneration but not for development of an epidermal barrier","volume":"108","author":"Kim","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/11\/876\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:30:56Z","timestamp":1760189456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/11\/876"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,31]]},"references-count":55,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["genes10110876"],"URL":"https:\/\/doi.org\/10.3390\/genes10110876","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,31]]}}}