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Intranuclear and higher‐order chromatin organization of the major histone gene cluster in breast cancer
Author(s) -
Fritz Andrew J.,
Ghule Prachi N.,
Boyd Joseph R.,
Tye Coralee E.,
Page Natalie A.,
Hong Deli,
Shirley David J.,
Weinheimer Adam S.,
Barutcu Ahmet R.,
Gerrard Diana L.,
Frietze Seth,
van Wijnen Andre J.,
Zaidi Sayyed K.,
Imbalzano Anthony N.,
Lian Jane B.,
Stein Janet L.,
Stein Gary S.
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.25996
Subject(s) - chromatin , histone , biology , ctcf , chromatin remodeling , bivalent chromatin , histone h1 , histone h2a , gene cluster , genetics , chia pet , histone code , gene , histone modifying enzymes , gene expression , cancer research , nucleosome , enhancer
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.