{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T16:53:21Z","timestamp":1774284801356,"version":"3.50.1"},"reference-count":77,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Singapore Ministry of Education Academic Research Fund Tier II","award":["MOE-T2EP30121-0018"],"award-info":[{"award-number":["MOE-T2EP30121-0018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Progesterone receptor (PR) regulates gene expression through recruiting coregulators and general transcription factors by activation functions AF1 and AF2. AF1 localizes to the non-conserved and disordered N-terminal domain and is believed to facilitate tissue- and gene-specific activity. Our previous proteomic analysis identified three key residues (K464, K481 and R492) in AF1 that are monomethylated. Methylation mimic mutations KKR \u2192 FFF created hypoactive PR, whereas the KKR \u2192 QQQ mutation generated hyperactive PR in gene reporter assays. The current study used these mutants to determine the roles of AF1 in PR regulation of cellular activities and global gene regulation in breast cancer cells MCF-7. AF1-FFF mutation attenuated PR regulation of cell proliferation and apoptosis in response to progestin, whereas AF1-QQQ mutation enhanced these effects. AF1-FFF mutation attenuated gene regulation by progestin in ~60% of PR target genes, including genes involved in cell proliferation, hypoxia and TNF\u03b1 signaling. However, the AF1-FFF mutation had little effect on ligand-independent gene regulation, suggesting distinct mechanisms of gene regulation by liganded and unliganded PR. Intriguingly, impaired activity of methylation mimic mutant PRB-FFF is associated with greater chromatin binding in ChIP-Seq analysis, corresponding to a stronger association between PRB-FFF and Steroid Receptor Coactivator-1 (SRC-1), a member of the p160 family of nuclear receptor coactivators, as was previously reported. In conclusion, PR AF1 is important for the core activities of liganded PR in regulating ~half of target genes and cell proliferation. AF1 monomethylation may modulate PR-chromatin interactions through stronger association with coregulators, thereby decelerating chromatin binding kinetics. This is supported by PRODIGY\u2019s prediction of higher binding affinities of monomethylated AF1 and methylation mimic mutant with SRC-1.<\/jats:p>","DOI":"10.3390\/ijms27062916","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T15:54:53Z","timestamp":1774281293000},"page":"2916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ligand-Dependent and -Independent Functions of Activation Function 1 of Progesterone Receptor in Genome-Wide Gene Regulation and in Cell Proliferation and Apoptosis of Breast Cancer Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Pheck Khee","family":"Lau","sequence":"first","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, Singapore 637511, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2709-1972","authenticated-orcid":false,"given":"Bernett Lee Teck","family":"Kwong","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637511, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shi Hao","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, Singapore 637511, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4529-2732","authenticated-orcid":false,"given":"Chew Leng","family":"Lim","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, Singapore 637511, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian Yee","family":"Woo","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, Singapore 637511, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4372-2532","authenticated-orcid":false,"given":"Amanda Rui En","family":"Woo","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, Singapore 637511, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9393-0802","authenticated-orcid":false,"given":"Jace","family":"Koh","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, Singapore 637511, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie C. L.","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, Singapore 637511, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"ref_1","first-page":"502","article-title":"Physiological Action of Progesterone in Target Tissues*","volume":"18","author":"Graham","year":"1997","journal-title":"Endocr. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1055\/s-0029-1242998","article-title":"Role of progesterone in endometrial cancer","volume":"28","author":"Kim","year":"2010","journal-title":"Semin. Reprod. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/nature09091","article-title":"Progesterone induces adult mammary stem cell expansion","volume":"465","author":"Joshi","year":"2010","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"641","DOI":"10.15252\/embj.201490434","article-title":"Progesterone and Wnt4 control mammary stem cells via myoepithelial crosstalk","volume":"34","author":"Rajaram","year":"2015","journal-title":"Embo J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1001\/jama.288.3.321","article-title":"Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women\u2019s Health Initiative randomized controlled trial","volume":"288","author":"Rossouw","year":"2002","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/S0140-6736(03)14596-5","article-title":"Breast cancer and hormone-replacement therapy in the Million Women Study","volume":"362","author":"Beral","year":"2003","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1097\/GME.0000000000002267","article-title":"Tis but a scratch: A critical review of the Women\u2019s Health Initiative evidence associating menopausal hormone therapy with the risk of breast cancer","volume":"30","author":"Bluming","year":"2023","journal-title":"Menopause"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1080\/13697137.2018.1514008","article-title":"Menopausal hormone therapy and breast cancer: What is the evidence from randomized trials?","volume":"21","author":"Hodis","year":"2018","journal-title":"Climacteric"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.maturitas.2006.05.004","article-title":"Prior hormone therapy and breast cancer risk in the Women\u2019s Health Initiative randomized trial of estrogen plus progestin","volume":"55","author":"Anderson","year":"2006","journal-title":"Maturitas"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1001\/jama.2013.278040","article-title":"Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women\u2019s Health Initiative randomized trials","volume":"310","author":"Manson","year":"2013","journal-title":"JAMA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.mce.2011.07.017","article-title":"Structural and Functional Analysis of Domains of the Progesterone Receptor","volume":"348","author":"Hill","year":"2012","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/333185a0","article-title":"The N-Terminal Region of the Chicken Progesterone-Receptor Specifies Target Gene Activation","volume":"333","author":"Tora","year":"1988","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/0092-8674(89)90031-7","article-title":"The human estrogen receptor has two independent nonacidic transcriptional activation functions","volume":"59","author":"Tora","year":"1989","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Jafari, H., Hussain, S., and Campbell, M.J. (2022). Nuclear Receptor Coregulators in Hormone-Dependent Cancers. Cancers, 14.","DOI":"10.3390\/cancers14102402"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/nrendo.2012.100","article-title":"Nuclear receptor coregulators: Modulators of pathology and therapeutic targets","volume":"8","author":"Lonard","year":"2012","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105321","DOI":"10.1016\/j.isci.2022.105321","article-title":"Spatial definition of the human progesterone receptor-B transcriptional complex","volume":"25","author":"Yu","year":"2022","journal-title":"iScience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"44546","DOI":"10.1074\/jbc.M112.411330","article-title":"Binding of the N-terminal region of coactivator TIF2 to the intrinsically disordered AF1 domain of the glucocorticoid receptor is accompanied by conformational reorganizations","volume":"287","author":"Khan","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1074\/jbc.M113.517896","article-title":"Acetylation at lysine 183 of progesterone receptor by p300 accelerates DNA binding kinetics and transactivation of direct target genes","volume":"289","author":"Chung","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.bbagrm.2019.01.004","article-title":"Delineation of critical amino acids in activation function 1 of progesterone receptor for recruitment of transcription coregulators","volume":"1862","author":"Woo","year":"2019","journal-title":"Biochim. Biophys. Acta Gene Regul. Mech."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lee, S.H., Lim, C.L., Shen, W., Tan, S.M.X., Woo, A.R.E., Yap, Y.H.Y., Sian, C.A.S., Goh, W.W.B., Yu, W.-P., and Li, L. (2022). Activation function 1 of progesterone receptor is required for progesterone antagonism of oestrogen action in the uterus. BMC Biol., 20.","DOI":"10.1186\/s12915-022-01410-3"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12286","DOI":"10.1038\/s41598-022-16289-x","article-title":"Activation function 1 of progesterone receptor is required for mammary development and regulation of RANKL during pregnancy","volume":"12","author":"Lee","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.ccr.2010.04.027","article-title":"Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor","volume":"17","author":"Andersen","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_23","first-page":"4607","article-title":"A new compound targets the AF-1 of androgen receptor and decreases its activity and protein levels in prostate cancer cells","volume":"10","author":"Tran","year":"2020","journal-title":"Am. J. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6390","DOI":"10.1038\/s41467-022-34077-z","article-title":"Small molecules targeting the disordered transactivation domain of the androgen receptor induce the formation of collapsed helical states","volume":"13","author":"Zhu","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/ijc.23081","article-title":"The activities of progesterone receptor isoform A and B are differentially modulated by their ligands in a gene-selective manner","volume":"122","author":"Leo","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17480","DOI":"10.1074\/jbc.M501261200","article-title":"A novel antiestrogenic mechanism in progesterone receptor-transfected breast cancer cells","volume":"280","author":"Zheng","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Bajalovic, N., Or, Y.Z., Woo, A.R.E., Lee, S.H., and Lin, V.C.L. (2022). High Levels of Progesterone Receptor B in MCF-7 Cells Enable Radical Anti-Tumoral and Anti-Estrogenic Effect of Progestin. Biomedicines, 10.","DOI":"10.3390\/biomedicines10081860"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1210\/mend.11.11.0006","article-title":"Biphasic regulation of breast cancer cell growth by progesterone: Role of the cyclin-dependent kinase inhibitors, p21 and p27(Kip1)","volume":"11","author":"Groshong","year":"1997","journal-title":"Mol. Endocrinol."},{"key":"ref_29","first-page":"5032","article-title":"Progestins Both Stimulate and Inhibit Breast-Cancer Cell-Cycle Progression While Increasing Expression of Transforming Growth Factor-Alpha, Epidermal Growth-Factor Receptor, C-Fos, and C-Myc Genes","volume":"11","author":"Musgrove","year":"1991","journal-title":"Mol. Cell. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4663","DOI":"10.1074\/jbc.M508342200","article-title":"Apoptotic cells, at all stages of the death process, trigger characteristic signaling events that are divergent from and dominant over those triggered by necrotic cells: Implications for the delayed clearance model of autoimmunity","volume":"281","author":"Patel","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.tips.2012.01.005","article-title":"Hypoxia-inducible factors: Mediators of cancer progression and targets for cancer therapy","volume":"33","author":"Semenza","year":"2012","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e159839","DOI":"10.1172\/JCI159839","article-title":"Hypoxia-inducible factors: Cancer progression and clinical translation","volume":"132","author":"Wicks","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"44446","DOI":"10.1038\/s41598-025-28183-3","article-title":"Proteomics analysis reveals progesterone receptor induced mitochondria-mediated apoptosis in breast cancer cells","volume":"15","author":"Woo","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/35083620","article-title":"Endonuclease G is an apoptotic DNase when released from mitochondria","volume":"412","author":"Li","year":"2001","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1074\/jbc.M109891200","article-title":"HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins","volume":"277","author":"Verhagen","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"46566","DOI":"10.1074\/jbc.M406317200","article-title":"Omi\/HtrA2 promotes cell death by binding and degrading the anti-apoptotic protein ped\/pea-15","volume":"279","author":"Trencia","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1128\/MCB.01539-06","article-title":"Progesterone Receptors Upregulate Wnt-1 To Induce Epidermal Growth Factor Receptor Transactivation and c-Src-Dependent Sustained Activation of Erk1\/2 Mitogen-Activated Protein Kinase in Breast Cancer Cells","volume":"27","author":"Faivre","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1128\/MCB.01246-10","article-title":"ck2-dependent phosphorylation of progesterone receptors (PR) on Ser81 regulates PR-B isoform-specific target gene expression in breast cancer cells","volume":"31","author":"Hagan","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1210\/me.2007-0443","article-title":"Progesterone Receptor Inhibits Aromatase and Inflammatory Response Pathways in Breast Cancer Cells via Ligand-Dependent and Ligand-Independent Mechanisms","volume":"22","author":"Hardy","year":"2008","journal-title":"Mol. Endocrinol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1038\/s42255-024-01060-5","article-title":"ASS1 metabolically contributes to the nuclear and cytosolic p53-mediated DNA damage response","volume":"6","author":"Lim","year":"2024","journal-title":"Nat. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1038\/s41419-021-04451-8","article-title":"Aldehyde dehydrogenase 3B2 promotes the proliferation and invasion of cholangiocarcinoma by increasing Integrin Beta 1 expression","volume":"12","author":"Wang","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5637","DOI":"10.1038\/s41467-022-33193-0","article-title":"Airway basal cells show a dedifferentiated KRT17(high)Phenotype and promote fibrosis in idiopathic pulmonary fibrosis","volume":"13","author":"Jaeger","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"14287","DOI":"10.1073\/pnas.0905118106","article-title":"Protein kinases mediate ligand-independent derepression of sumoylated progesterone receptors in breast cancer cells","volume":"106","author":"Daniel","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1210\/me.2004-0287","article-title":"Progesterone-independent effects of human progesterone receptors (PRs) in estrogen receptor-positive breast cancer: PR isoform-specific gene regulation and tumor biology","volume":"19","author":"Jacobsen","year":"2005","journal-title":"Mol. Endocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nature14583","article-title":"Progesterone receptor modulates ER\u03b1 action in breast cancer","volume":"523","author":"Mohammed","year":"2015","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e1501924","DOI":"10.1126\/sciadv.1501924","article-title":"Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer","volume":"2","author":"Singhal","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Yin, P., Roqueiro, D., Huang, L., Owen, J.K., Xie, A., Navarro, A., Monsivais, D., Coon, J.S., Kim, J.J., and Dai, Y. (2012). Genome-Wide Progesterone Receptor Binding: Cell Type-Specific and Shared Mechanisms in T47D Breast Cancer Cells and Primary Leiomyoma Cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0029021"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"12716","DOI":"10.1093\/nar\/gkab1125","article-title":"A set of accessible enhancers enables the initial response of breast cancer cells to physiological progestin concentrations","volume":"49","author":"Zaurin","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1210\/me.2007-0437","article-title":"Progesterone receptor rapid signaling mediates serine 345 phosphorylation and tethering to specificity protein 1 transcription factors","volume":"22","author":"Faivre","year":"2008","journal-title":"Mol. Endocrinol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Singh, M., Krishnamoorthy, V.R., Kim, S., Khurana, S., and LaPorte, H.M. (2024). Brain-derived neuerotrophic factor and related mechanisms that mediate and influence progesterone-induced neuroprotection. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1286066"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1242\/dev.043299","article-title":"FOXA1 is an essential determinant of ER alpha expression and mammary ductal morphogenesis","volume":"137","author":"Bernardo","year":"2010","journal-title":"Development"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Clarke, C.L., and Graham, J.D. (2012). Non-overlapping progesterone receptor cistromes contribute to cell-specific transcriptional outcomes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035859"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s001090050241","article-title":"Ligand-independent activation of steroid hormone receptors","volume":"76","author":"Weigel","year":"1998","journal-title":"J. Mol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1093\/emboj\/16.6.1427","article-title":"Ligand-independent activation of the oestrogen receptor by mutation of a conserved tyrosine","volume":"16","author":"White","year":"1997","journal-title":"Embo J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1016\/j.bbamcr.2014.04.008","article-title":"Protein arginine methyltransferase 6 enhances ligand-dependent and -independent activity of estrogen receptor alpha via distinct mechanisms","volume":"1843","author":"Sun","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.molcel.2009.09.005","article-title":"Transcription dynamics","volume":"35","author":"Hager","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"10897","DOI":"10.1093\/nar\/gkae714","article-title":"Unexpected nuclear hormone receptor and chromatin dynamics regulate estrous cycle dependent gene expression","volume":"52","author":"Jefferson","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/s00412-010-0283-8","article-title":"Dynamics of nuclear receptor target gene regulation","volume":"119","author":"Carlberg","year":"2010","journal-title":"Chromosoma"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0092-8674(02)00860-7","article-title":"Dynamic remodeling of transcription complexes by molecular chaperones","volume":"110","author":"Morimoto","year":"2002","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1126\/science.adg3797","article-title":"Linking genome structures to functions by simultaneous single-cell Hi-C and RNA-seq","volume":"380","author":"Liu","year":"2023","journal-title":"Science"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5704","DOI":"10.1074\/jbc.M113.522839","article-title":"Lysine methylation of progesterone receptor at activation function 1 regulates both ligand-independent activity and ligand sensitivity of the receptor","volume":"289","author":"Chung","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.str.2014.04.013","article-title":"Influence of domain interactions on conformational mobility of the progesterone receptor detected by hydrogen\/deuterium exchange mass spectrometry","volume":"22","author":"Goswami","year":"2014","journal-title":"Structure"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1038\/s12276-024-01233-y","article-title":"Enhancer-promoter specificity in gene transcription: Molecular mechanisms and disease associations","volume":"56","author":"Friedman","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"8383","DOI":"10.1128\/MCB.19.12.8383","article-title":"The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1","volume":"19","author":"Bevan","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e07454","DOI":"10.7554\/eLife.07454","article-title":"Contacts-based prediction of binding affinity in protein-protein complexes","volume":"4","author":"Vangone","year":"2015","journal-title":"Elife"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3676","DOI":"10.1093\/bioinformatics\/btw514","article-title":"PRODIGY: A web server for predicting the binding affinity of protein-protein complexes","volume":"32","author":"Xue","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.12688\/f1000research.7563.1","article-title":"Differential analyses for RNA-seq: Transcript-level estimates improve gene-level inferences","volume":"4","author":"Soneson","year":"2015","journal-title":"F1000Res"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"R137","DOI":"10.1186\/gb-2008-9-9-r137","article-title":"Model-based analysis of ChIP-Seq (MACS)","volume":"9","author":"Zhang","year":"2008","journal-title":"Genome Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nbt.1754","article-title":"Integrative genomics viewer","volume":"29","author":"Robinson","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/978-1-0716-4071-5_5","article-title":"Differential Analysis of Protein-DNA Binding Using ChIP-Seq Data","volume":"2846","author":"Boeckel","year":"2024","journal-title":"Methods Mol. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"W345","DOI":"10.1093\/nar\/gkac247","article-title":"The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2022 update","volume":"50","author":"Galaxy","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"W39","DOI":"10.1093\/nar\/gkv416","article-title":"The MEME Suite","volume":"43","author":"Bailey","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"R83","DOI":"10.1186\/gb-2011-12-8-r83","article-title":"Cistrome: An integrative platform for transcriptional regulation studies","volume":"12","author":"Liu","year":"2011","journal-title":"Genome Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2916\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T15:56:07Z","timestamp":1774281367000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2916"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,23]]},"references-count":77,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062916"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062916","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,23]]}}}