{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T17:47:38Z","timestamp":1745948858673,"version":"3.37.3"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2019,11,5]],"date-time":"2019-11-05T00:00:00Z","timestamp":1572912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["RO1CA140663","R15CA235430","K22CA204439"],"award-info":[{"award-number":["RO1CA140663","R15CA235430","K22CA204439"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005825","name":"USDA NIFA","doi-asserted-by":"crossref","award":["Hatch-NEV00727","Hatch-NEV00767","NIH P20 GM130459","R15 HL143496"],"award-info":[{"award-number":["Hatch-NEV00727","Hatch-NEV00767","NIH P20 GM130459","R15 HL143496"]}],"id":[{"id":"10.13039\/100005825","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Our previous study has shown that ERBB2 is overexpressed in the organoid model of MCF10A when the stiffness of the microenvironment is increased to that of high mammographic density (MD). We now aim to identify key transcription factors (TFs) and functional enhancers that regulate processes associated with increased stiffness of the microenvironment in the organoid models of premalignant human mammary cell lines.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>3D colony organizations and the cis-regulatory networks of two human mammary epithelial cell lines (184A1 and MCF10A) are investigated as a function of the increased stiffness of the microenvironment within the range of MD. The 3D colonies are imaged using confocal microscopy, and the morphometries of colony organizations and heterogeneity are quantified as a function of the stiffness of the microenvironment using BioSig3D. In a surrogate assay, colony organizations are profiled by transcriptomics. Transcriptome data are enriched by correlative analysis with the computed morphometric indices. Next, a subset of enriched data are processed against publicly available ChIP-Seq data using Model-based Analysis of Regulation of Gene Expression to predict regulatory transcription factors. This integrative analysis of morphometric and transcriptomic data predicted YY1 as one of the cis-regulators in both cell lines as a result of the increased stiffness of the microenvironment. Subsequent experiments validated that YY1 is expressed at protein and mRNA levels for MCF10A and 184A1, respectively. Also, there is a causal relationship between activation of YY1 and ERBB2 when YY1 is overexpressed at the protein level in MCF10A.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btz812","type":"journal-article","created":{"date-parts":[[2019,10,30]],"date-time":"2019-10-30T20:12:10Z","timestamp":1572466330000},"page":"1663-1667","source":"Crossref","is-referenced-by-count":8,"title":["YY1 is a <i>cis<\/i>-regulator in the organoid models of high mammographic density"],"prefix":"10.1093","volume":"36","author":[{"given":"Qingsu","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Electrical and Biomedical Engineering, University of Nevada , Reno, NV 22908, USA"}]},{"given":"Mina","family":"Khoshdeli","sequence":"additional","affiliation":[{"name":"Department of Electrical and Biomedical Engineering, University of Nevada , Reno, NV 22908, USA"}]},{"given":"Bradley S","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Department of Nutrition, University Of Nevada , Reno, NV 22908, USA"},{"name":"Department of Public Health, Center of Biomedical Research Excellence for Molecular and Cellular Signal Transduction in the Cardiovascular System, University of Nevada , Reno, NV 22908, USA"}]},{"given":"Kosar","family":"Jabbari","sequence":"additional","affiliation":[{"name":"Department of Electrical and Biomedical Engineering, University of Nevada , Reno, NV 22908, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4812-3627","authenticated-orcid":false,"given":"Chongzhi","family":"Zang","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia , Charlottesville, VA 22908, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6433-8006","authenticated-orcid":false,"given":"Bahram","family":"Parvin","sequence":"additional","affiliation":[{"name":"Department of Electrical and Biomedical Engineering, University of Nevada , Reno, NV 22908, USA"}]}],"member":"286","published-online":{"date-parts":[[2019,11,5]]},"reference":[{"key":"2023060911575742700_btz812-B1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/bcr1851","article-title":"The combined immunodetection of AP-2alpha and YY1 transcription factors is associated with ERBB2 gene overexpression in primary breast tumors","volume":"10","author":"Allouche","year":"2008","journal-title":"Breast Cancer Res"},{"key":"2023060911575742700_btz812-B2","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1158\/2159-8290.CD-17-0151","article-title":"AACR project GENIE: powering precision medicine through an international consortium","volume":"7","author":"Andre","year":"2017","journal-title":"Cancer Discov"},{"key":"2023060911575742700_btz812-B3","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1615\/CritRevOncog.v16.i3-4.20","article-title":"Mechanisms of Yin Yang 1 in oncogenesis: the importance of indirect effects","volume":"16","author":"Atchison","year":"2011","journal-title":"Crit. Rev. Oncog"},{"key":"2023060911575742700_btz812-B4","doi-asserted-by":"crossref","first-page":"24428","DOI":"10.1074\/jbc.M503790200","article-title":"Yin Yang 1 cooperates with activator protein 2 to stimulate ERBB2 gene expression in mammary cancer cells","volume":"280","author":"Begon","year":"2005","journal-title":"J. Biol. Chem"},{"key":"2023060911575742700_btz812-B5","doi-asserted-by":"crossref","first-page":"3087","DOI":"10.1093\/bioinformatics\/btt535","article-title":"Integrated profiling of three dimensional cell culture models and 3D microscopy","volume":"29","author":"Bilgin","year":"2013","journal-title":"Bioinformatics"},{"key":"2023060911575742700_btz812-B6","doi-asserted-by":"crossref","first-page":"e0148379","DOI":"10.1371\/journal.pone.0148379","article-title":"BioSig3D: high content screening of three-dimensional cell culture models","volume":"11","author":"Bilgin","year":"2016","journal-title":"PLoS One"},{"key":"2023060911575742700_btz812-B7","doi-asserted-by":"crossref","first-page":"28987","DOI":"10.1038\/srep28987","article-title":"Stiffness of the microenvironment upregulates ERBB2 expression in 3D cultures of MCF10A within the range of mammographic density","volume":"6","author":"Cheng","year":"2016","journal-title":"Sci. Rep"},{"key":"2023060911575742700_btz812-B8","doi-asserted-by":"crossref","first-page":"21931","DOI":"10.1073\/pnas.1016071107","article-title":"Histone H3K27ac separates active from poised enhancers and predicts developmental state","volume":"107","author":"Creyghton","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023060911575742700_btz812-B9","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.canlet.2018.06.021","article-title":"Agave negatively regulates YAP and TAZ transcriptionally and post-translationally in osteosarcoma cell lines","volume":"433","author":"Ferraiuolo","year":"2018","journal-title":"Cancer Lett"},{"key":"2023060911575742700_btz812-B10","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nrm3416","article-title":"Transduction of mechanical and cytoskeletal cues by YAP and TAZ","volume":"13","author":"Halder","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol"},{"key":"2023060911575742700_btz812-B11","doi-asserted-by":"crossref","first-page":"e1000684","DOI":"10.1371\/journal.pcbi.1000684","article-title":"Molecular Predictors of 3D morphogenesis by breast cancer cells in 3D culture","volume":"6","author":"Han","year":"2010","journal-title":"PLoS Comput. Biol"},{"key":"2023060911575742700_btz812-B12","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/nrc3458","article-title":"The Hippo pathway and human cancer","volume":"13","author":"Harvey","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"2023060911575742700_btz812-B13","doi-asserted-by":"crossref","first-page":"2916","DOI":"10.1016\/j.yexcr.2013.09.018","article-title":"Substrate stiffness regulates temporary NF-kappaB activation via actomyosin contractions","volume":"319","author":"Ishihara","year":"2013","journal-title":"Exp. Cell Res"},{"key":"2023060911575742700_btz812-B14","doi-asserted-by":"crossref","first-page":"71","DOI":"10.18632\/genesandcancer.12","article-title":"Role of YY1 in the pathogenesis of prostate cancer and correlation with bioinformatic data sets of gene expression","volume":"5","author":"Kashyap","year":"2014","journal-title":"Genes Cancer"},{"key":"2023060911575742700_btz812-B15","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nmeth1015","article-title":"Three-dimensional culture models of normal and malignant breast epithelial cells","volume":"4","author":"Lee","year":"2007","journal-title":"Nat. Method"},{"key":"2023060911575742700_btz812-B16","doi-asserted-by":"crossref","first-page":"3946","DOI":"10.1091\/mbc.E15-07-0456","article-title":"Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors","volume":"26","author":"Lin","year":"2015","journal-title":"Mol. Biol. Cell"},{"key":"2023060911575742700_btz812-B17","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.cell.2013.03.036","article-title":"Selective inhibition of tumor oncogenes by disruption of super-enhancers","volume":"153","author":"Loven","year":"2013","journal-title":"Cell"},{"key":"2023060911575742700_btz812-B18","first-page":"3061","article-title":"Mechanosensitive mechanisms in transcriptional regulation","volume":"125","author":"Mammoto","year":"2012","journal-title":"J. Cell Sci"},{"key":"2023060911575742700_btz812-B19","doi-asserted-by":"crossref","first-page":"D658","DOI":"10.1093\/nar\/gkw983","article-title":"Cistrome Data Browser: a data portal for ChIP-Seq and chromatin accessibility data in human and mouse","volume":"45","author":"Mei","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2023060911575742700_btz812-B20","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.7150\/jca.19036","article-title":"Identification of transcription factor YY1 as a regulator of a prostate cancer-specific pathway using proteomic analysis","volume":"8","author":"Park","year":"2017","journal-title":"J. Cancer"},{"key":"2023060911575742700_btz812-B21","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/nature13986","article-title":"Topologically associating domains are stable units of replication-timing regulation","volume":"515","author":"Pope","year":"2014","journal-title":"Nature"},{"key":"2023060911575742700_btz812-B22","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/nature09692","article-title":"A unique chromatin signature uncovers early developmental enhancers in humans","volume":"470","author":"Rada-Iglesias","year":"2011","journal-title":"Nature"},{"key":"2023060911575742700_btz812-B23","first-page":"7487","article-title":"Yin-yang 1 activates the c-myc promoter","volume":"13","author":"Riggs","year":"1993","journal-title":"Mol. Cell. Biol"},{"key":"2023060911575742700_btz812-B24","doi-asserted-by":"crossref","first-page":"790","DOI":"10.15252\/msb.20145644","article-title":"Cell shape and the microenvironment regulate nuclear translocation of NF-kappaB in breast epithelial and tumor cells","volume":"11","author":"Sero","year":"2015","journal-title":"Mol. Syst. Biol"},{"key":"2023060911575742700_btz812-B25","first-page":"6075","article-title":"Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10","volume":"50","author":"Soule","year":"1990","journal-title":"Cancer Res"},{"key":"2023060911575742700_btz812-B26","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1016\/j.ajpath.2012.01.037","article-title":"Yin Yang 1 plays an essential role in breast cancer and negatively regulates p27","volume":"180","author":"Wan","year":"2012","journal-title":"Am. J. Pathol"},{"key":"2023060911575742700_btz812-B27","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1101\/gr.201574.115","article-title":"Modeling cis-regulation with a compendium of genome-wide histone H3K27ac profiles","volume":"26","author":"Wang","year":"2016","journal-title":"Genome Res"},{"key":"2023060911575742700_btz812-B28","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1093\/bioinformatics\/bty194","article-title":"BART: a transcription factor prediction tool with query gene sets or epigenomic profiles","volume":"34","author":"Wang","year":"2018","journal-title":"Bioinformatics"},{"key":"2023060911575742700_btz812-B29","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.bbrc.2005.07.150","article-title":"Nucleophosmin\/B23 regulates PCNA promoter through YY1","volume":"335","author":"Weng","year":"2005","journal-title":"Biochem. Biophys. Res. Commun"},{"key":"2023060911575742700_btz812-B30","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.cell.2013.03.035","article-title":"Master transcription factors and mediator establish super-enhancers at key cell identity genes","volume":"153","author":"Whyte","year":"2013","journal-title":"Cell"},{"key":"2023060911575742700_btz812-B31","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1093\/carcin\/18.4.605","article-title":"Which DNA polymerases are used for DNA-repair in eukaryotes?","volume":"18","author":"Wood","year":"1997","journal-title":"Carcinogenesis"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btz812\/30384348\/btz812.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/6\/1663\/50554094\/bioinformatics_36_6_1663.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/6\/1663\/50554094\/bioinformatics_36_6_1663.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T11:58:50Z","timestamp":1686311930000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/36\/6\/1663\/5613181"}},"subtitle":[],"editor":[{"given":"Robert","family":"Murphy","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2019,11,5]]},"references-count":31,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,3,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btz812","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"type":"print","value":"1367-4803"},{"type":"electronic","value":"1367-4811"}],"subject":[],"published-other":{"date-parts":[[2020,3,15]]},"published":{"date-parts":[[2019,11,5]]}}}