title: Spatiotemporal control of estrogen-responsive transcription in ERα-positive breast cancer cells.
abstract: Recruitment of transcription machinery to target promoters for aberrant gene expression has been well studied, but underlying control directed by distant-acting enhancers remains unclear in cancer development. Our previous study demonstrated that distant estrogen response elements (DEREs) located on chromosome 20q13 are frequently amplified and translocated to other chromosomes in ERα-positive breast cancer cells. In this study, we used three-dimensional interphase fluorescence in situ hybridization to decipher spatiotemporal gathering of multiple DEREs in the nucleus. Upon estrogen stimulation, scattered 20q13 DEREs were mobilized to form regulatory depots for synchronized gene expression of target loci. A chromosome conformation capture assay coupled with chromatin immunoprecipitation further uncovered that ERα-bound regulatory depots are tethered to heterochromatin protein 1 (HP1) for coordinated chromatin movement and histone modifications of target loci, resulting in transcription repression. Neutralizing HP1 function dysregulated the formation of DERE-involved regulatory depots and transcription inactivation of candidate tumor-suppressor genes. Deletion of amplified DEREs using the CRISPR/Cas9 genomic-editing system profoundly altered transcriptional profiles of proliferation-associated signaling networks, resulting in reduction of cancer cell growth. These findings reveal a formerly uncharacterized feature wherein multiple copies of the amplicon congregate as transcriptional units in the nucleus for synchronous regulation of function-related loci in tumorigenesis. Disruption of their assembly can be a new strategy for treating breast cancers and other malignancies.
authors: Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: P-Y
authors: PY
authors: Hsu
authors: Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: H-K
authors: HK
authors: Hsu
authors: Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Department of Medical Research, Taichung Veterans General Hospital, Taichung City, Taiwan.
authors: T-H
authors: TH
authors: Hsiao
authors: Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: Z
authors: Z
authors: Ye
authors: Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: E
authors: E
authors: Wang
authors: Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Department of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: A L
authors: AL
authors: Profit
authors: Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Department of Surgery, The University of Texas Health Science Center at San Antonio, San Antonio TX, USA.
authors: I
authors: I
authors: Jatoi
authors: Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Department of Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: Y
authors: Y
authors: Chen
authors: Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: N B
authors: NB
authors: Kirma
authors: Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Department of Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: V X
authors: VX
authors: Jin
authors: Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: Z D
authors: ZD
authors: Sharp
authors: Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: T H-M
authors: TH
authors: Huang
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D019295:Computational Biology; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D020218:Response Elements / Q000235:genetics*; D050791:STAT Transcription Factors / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics; D062211:Spatio-Temporal Analysis; D016019:Survival Analysis; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D047628:Estrogen Receptor alpha; D004967:Estrogens; D051741:Kruppel-Like Transcription Factors; D050791:STAT Transcription Factors; C408894:ZIM2 protein, human; D000090266:Chromobox Protein Homolog 5; D053612:Janus Kinases