title: SATB1 Mediates Long-Range Chromatin Interactions: A Dual Regulator of Anti-Apoptotic BCL2 and Pro-Apoptotic NOXA Genes.
abstract: Aberrant expression of special AT-rich binding protein 1 (SATB1), a global genomic organizer, has been associated with various cancers, which raises the question of how higher-order chromatin structure contributes to carcinogenesis. Disruption of apoptosis is one of the hallmarks of cancer. We previously demonstrated that SATB1 mediated specific long-range chromosomal interactions between the mbr enhancer located within 3'-UTR of the BCL2 gene and the promoter to regulate BCL2 expression during early apoptosis. In the present study, we used chromosome conformation capture (3C) assays and molecular analyses to further investigate the function of the SATB1-mediated higher-order chromatin structure in co-regulation of the anti-apoptotic BCL2 gene and the pro-apoptotic NOXA gene located 3.4Mb downstream on Chromosome 18. We demonstrated that the mbr enhancer spatially juxtaposed the promoters of BCL2 and NOXA genes through SATB1-mediated chromatin-loop in Jurkat cells. Decreased SATB1 levels switched the mbr-BCL2 loop to mbr-NOXA loop, and thus changed expression of these two genes. The SATB1-mediated dynamic switch of the chromatin loop structures was essential for the cooperative expression of the BCL2 and NOXA genes in apoptosis. Notably, the role of SATB1 was specific, since inhibition of SATB1 degradation by caspase-6 inhibitor or caspase-6-resistant SATB1 mutant reversed expression of BCL-2 and NOXA in response to apoptotic stimulation. This study reveals the critical role of SATB1-organized higher-order chromatin structure in regulating the dynamic equilibrium of apoptosis-controlling genes with antagonistic functions and suggests that aberrant SATB1 expression might contribute to cancer development by disrupting the co-regulated genes in apoptosis pathways.
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing medical University, Nanjing, PR China; Department of Cell Biology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing medical University, Nanjing, PR China; Department of Cell Biology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Zongdan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing medical University, Nanjing, PR China; Department of Cell Biology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Luan
authors.initials: L
authors.lastname: Sun
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing medical University, Nanjing, PR China; Department of Cell Biology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Lipei
authors.initials: L
authors.lastname: Shao
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing medical University, Nanjing, PR China; Department of Cell Biology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing medical University, Nanjing, PR China; Department of Cell Biology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Physiology and Stephenson Cancer Center, University of Oklahoma Health Sciences Center, University of Oklahoma, Norman, Oklahoma, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing medical University, Nanjing, PR China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing medical University, Nanjing, PR China; Department of Cell Biology, Nanjing Medical University, Nanjing, PR China; Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, Nanjing Medical University, Nanjing, PR China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Sun
mesh_terms: D017209:Apoptosis; D002843:Chromatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*
chemical_list: D002843:Chromatin; D036961:Matrix Attachment Region Binding Proteins; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C076189:SATB1 protein, human