The subnuclear organization of histone gene regulatory proteins and 3' end processing factors of normal somatic and embryonic stem cells is compromised in selected human cancer cell types

Abstract

Human histone gene expression is controlled at the level of transcription initiation and subsequent 3'end processing to generate non-polyadenylated stem-loop containing histone mRNAs. Transcription is controlled at the G1/S phase transition by the Cyclin E/CDK2 mediated induction of p220(NPAT)/HiNF-P complexes at subnuclear domains designated Histone Locus Bodies (HLBs) that associate with histone gene clusters. Histone mRNA maturation is mediated by Lsm10 containing U7snRNP complexes. In normal human somatic and embryonic stem cells, the 6p histone locus, the transcription marker p220(NPAT) and the 3'end processing marker Lsm10 (but not the Cajal Body marker coilin) co-localize, reflecting the assembly of an integrated factory for histone gene expression. Using in situ immuno-fluorescence microscopy and fluorescence in situ hybridization (FISH), we show that this subnuclear organization is compromised in some cancer cell lines. In aneuploid cells, the presence of HLBs correlates with the number of histone gene loci. More importantly, the in situ co-localization of p220(NPAT) and Lsm10 is disrupted in HeLa S3 cervical carcinoma cells and MCF7 breast adenocarcinoma cells, with most Lsm10 residing in Cajal Bodies. The finding that the subnuclear integration of transcriptional initiation and 3'end processing of histone gene transcripts is deregulated may be causally linked to tumor-related modifications in molecular pathways controlling histone gene expression during the cell cycle.