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Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster
Author(s) -
Mishiro Tsuyoshi,
Ishihara Ko,
Hino Shinjiro,
Tsutsumi Shuichi,
Aburatani Hiroyuki,
Shirahige Katsuhiko,
Kinoshita Yoshikazu,
Nakao Mitsuyoshi
Publication year - 2009
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.81
Subject(s) - biology , chromatin , genetics , cluster (spacecraft) , gene cluster , gene , chia pet , computational biology , chromatin remodeling , computer science , programming language
Long‐range regulatory elements and higher‐order chromatin structure coordinate the expression of multiple genes in cluster, and CTCF/cohesin‐mediated chromatin insulator may be a key in this regulation. The human apolipoprotein ( APO ) A1 / C3 / A4 / A5 gene region, whose alterations increase the risk of dyslipidemia and atherosclerosis, is partitioned at least by three CTCF‐enriched sites and three cohesin protein RAD21‐enriched sites (two overlap with the CTCF sites), resulting in the formation of two transcribed chromatin loops by interactions between insulators. The C3 enhancer and APOC3 / A4 / A5 promoters reside in the same loop, where the APOC3 / A4 promoters are pointed towards the C3 enhancer, whereas the APOA1 promoter is present in the different loop. The depletion of either CTCF or RAD21 disrupts the chromatin loop structure, together with significant changes in the APO expression and the localization of transcription factor hepatocyte nuclear factor (HNF)‐4α and transcriptionally active form of RNA polymerase II at the APO promoters. Thus, CTCF/cohesin‐mediated insulators maintain the chromatin loop formation and the localization of transcriptional apparatus at the promoters, suggesting an essential role of chromatin insulation in controlling the expression of clustered genes.