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J Cell Physiol. 2018 Feb;233(2):1278-1290. doi: 10.1002/jcp.25996. Epub 2017 Jun 22.

Intranuclear and higher-order chromatin organization of the major histone gene cluster in breast cancer.

Author information

1
Department of Biochemistry and University of Vermont Cancer Center, The University of Vermont Larner College of Medicine, Burlington, Vermont.
2
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
3
Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont.
4
Medical Laboratory and Radiation Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, Vermont.
5
Department of Orthopedic Surgery and Biochemistry & Molecular Biology, Mayo Clinic, Rochester, Minnesota.
6
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts.

Abstract

Alterations in nuclear morphology are common in cancer progression. However, the degree to which gross morphological abnormalities translate into compromised higher-order chromatin organization is poorly understood. To explore the functional links between gene expression and chromatin structure in breast cancer, we performed RNA-seq gene expression analysis on the basal breast cancer progression model based on human MCF10A cells. Positional gene enrichment identified the major histone gene cluster at chromosome 6p22 as one of the most significantly upregulated (and not amplified) clusters of genes from the normal-like MCF10A to premalignant MCF10AT1 and metastatic MCF10CA1a cells. This cluster is subdivided into three sub-clusters of histone genes that are organized into hierarchical topologically associating domains (TADs). Interestingly, the sub-clusters of histone genes are located at TAD boundaries and interact more frequently with each other than the regions in-between them, suggesting that the histone sub-clusters form an active chromatin hub. The anchor sites of loops within this hub are occupied by CTCF, a known chromatin organizer. These histone genes are transcribed and processed at a specific sub-nuclear microenvironment termed the major histone locus body (HLB). While the overall chromatin structure of the major HLB is maintained across breast cancer progression, we detected alterations in its structure that may relate to gene expression. Importantly, breast tumor specimens also exhibit a coordinate pattern of upregulation across the major histone gene cluster. Our results provide a novel insight into the connection between the higher-order chromatin organization of the major HLB and its regulation during breast cancer progression.

KEYWORDS:

CTCF; breast cancer progression; cell cycle control; higher-order chromatin organization; histone locus body

PMID:
28504305
PMCID:
PMC5705002
DOI:
10.1002/jcp.25996
[Indexed for MEDLINE]
Free PMC Article

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