Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster.
Journal: 2009/May - EMBO Journal
ISSN: 1460-2075
Abstract:
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)-4alpha 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.
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EMBO J 28(9): 1234-1245

Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster

Supplementary Material

Supplementary Figures S1–S8

Supplementary Table 1

Supplementary Information

Department of Regeneration Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Japan
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Komaba, Meguro-ku, Tokyo, Japan
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama City, Kanagawa, Japan
Department of Regeneration Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan. Tel.: +81 96 373 6800; Fax: +81 96 373 6804; E-mail: pj.ca.u-otomamuk.opg@oakanm
Received 2008 Dec 29; Accepted 2009 Mar 4.

Abstract

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.

Keywords: apolipoprotein, cohesin, CTCF, enhancer, insulator
Abstract
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Acknowledgments

We appreciate Dr Jan-Michael Peters (Research Institute of Molecular Pathology) for collaboration using ChIP-on-chip analyses, and the members in our laboratory for helpful discussions. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology (MN), by a Grant-in-Aid for the Global Center of Excellence (COE) ‘Cell Fate Regulation Research and Education Unit', Kumamoto University, and in part by a research grant from the Uehara Memorial Foundation (MN).

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