title: The BCL2 gene is regulated by a special AT-rich sequence binding protein 1-mediated long range chromosomal interaction between the promoter and the distal element located within the 3'-UTR.
abstract: The 279-bp major breakpoint region (mbr) within the 3'-untranslated region (3'-UTR) of the BCL2 gene is a binding site of special AT-rich sequence binding protein 1 (SATB1) that is well known to participate in the long-range regulation of gene transcription. Our previous studies have revealed that the mbr could regulate BCL2 transcription over a 200-kb distance and this regulatory function was closely related to SATB1. This study is to explore the underlying mechanism and its relevance to cellular apoptosis. With chromosome conformation capture (3C) and chromatin immunoprecipitation (ChIP) assays we demonstrated that the mbr could physically interact with BCL2 promoter through SATB1-mediated chromatin looping, which was required for epigenetic modifications of the promoter, CREB accessibility and high expression of the BCL2 gene. During early apoptosis, SATB1 was a key regulator of BCL2 expression. Inhibition of SATB1 cleavage by treatment of cells with a caspase-6 inhibitor or overexpression of mutant SATB1 that was resistant to caspase-6, inhibited disassembly of the SATB1-mediated chromatin loop and restored the BCL2 mRNA level in Jurkat cells. These data revealed a novel mechanism of BCL2 regulation and mechanistically link SATB1-mediated long-range interaction with the regulation of a gene controlling apoptosis pathway for the first time.
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Cell Biology and Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, Nanjing Medical University, Nanjing 210029, PR China.
authors.forename: Feiran
authors.initials: F
authors.lastname: Gong
authors.forename: Luan
authors.initials: L
authors.lastname: Sun
authors.forename: Zongdan
authors.initials: Z
authors.lastname: Wang
authors.forename: Junfeng
authors.initials: J
authors.lastname: Shi
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Sumeng
authors.initials: S
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.forename: Yujie
authors.initials: Y
authors.lastname: Sun
mesh_terms: D020413:3' Untranslated Regions; D017209:Apoptosis; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002875:Chromosomes / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D019169:Jurkat Cells; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism* / Q000502:physiology; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D022782:CCAAT-Enhancer-Binding Protein-beta; D017362:Cyclic AMP Response Element-Binding Protein; D036961:Matrix Attachment Region Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C076189:SATB1 protein, human; D050880:p300-CBP Transcription Factors