Project description:Transcription and processing of histone mRNAs occurs at subnuclear domains known as Histone Locus Bodies (HLBs). Although it is known that higher-order chromatin organization is dysregulated in cancer, structural alterations within HLB across breast cancer progression are unclear. Differential expression across known as MCF10, a basal triple negative breast cancer progression model, followed by pathway analysis demonstrated many alterations in signaling cascades known to be related to proliferation. Positional gene enrichment identified the hist1 gene locus at chromosome 6p22 as the most significantly altered cluster of genes from the normal-like MCF10A to premalignant MCF10AT1. The malignant MCF10CA1a had a more varied expression pattern across the hist1 locus. Within this region there are three subclusters of hist1 genes which were generally upregulated while intervening genes were more frequently downregulated. Extending these findings to TCGA breast tumors revealed that normal adjacent tissue had lower expression within the subclusters than their matched tumor samples. Moreover, the expression pattern within the hist1 locus comparing normal versus tumors recapitulated a very similar pattern to that comparing 10A to AT1 or CA1a. Since the hist1 locus is transcribed and processed at a specific subnuclear microenvironment, the higher order chromatin organization of this locus may be a critical component of its regulation. We addressed whether CTCF, a key chromatin organizing protein, may play a role in organizing the hist1 HLB. Immunofluorescence for CTCF along with NPAT, a protein which decorates this locus, identified that CTCF may tether the hist1 HLB to the nuclear matrix. All three subclusters reside within a single topologically associating domain wherein interacting loops are bound by CTCF. Inter-subcluster interactions are lost in the premalignant AT1. Consistent with the varied expression across the hist1 HLB in CA1a, inter-subcluster interactions are regained in the malignant state. These data suggest a transient state in highly proliferative breast cancer cells in which the hist1 HLB is dynamically reorganized.

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SUMO2 Regulates Histone Pre-mRNA Processing by Stabilizing Histone Locus Body Interactions and Promoting U7 snRNP Assembly

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