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Background  The three members of the human heterochromatin protein 1 (HP1) family of proteins, HP1α, HP1β, and HPγ, are involved in chromatin packing and epigenetic gene regulation. HP1α is encoded from the  CBX5  gene and is a suppressor of metastasis.  CBX5  is down-regulated at the transcriptional and protein level in metastatic compared to non-metastatic breast cancer.  CBX5  shares a bi-directional promoter structure with the  hnRNPA1  gene. But whereas  CBX5  expression is down-regulated in metastatic cells,  hnRNAP1  expression is constant. Here, we address the regulation of  CBX5  in human breast cancer.    Methods  Transient transfection and transposon mediated integration of dual-reporter mini-genes containing the bi-directional  hnRNPA1  and  CBX5  promoter was performed to investigate transcriptional regulation in breast cancer cell lines. Bioinformatics and functional analysis were performed to characterize transcriptional events specifically regulating  CBX5  expression. TSA treatment and Chromatin Immunoprecipitation (ChIP) were performed to investigate the chromatin structure along  CBX5  in breast cancer cells. Finally, expression of  hnRNPA1  and  CBX5  mRNA isoforms were measured by quantitative reverse transcriptase PCR (qRT-PCR) in breast cancer tissue samples.    Results  We demonstrate that an  hnRNPA1  and  CBX5  bi-directional core promoter fragment does not comprise intrinsic capacity for specific  CBX5  down-regulation in metastatic cells. Characterization of transcriptional events in the 20 kb  CBX5  intron 1 revealed existence of several novel  CBX5  transcripts. Two of these encode consensus HP1α protein but used autonomous promoters in intron 1 by which HP1α expression could be de-coupled from the bi-directional promoter. In addition, another  CBX5  transcriptional isoform,  STET , was discovered. This transcript includes  CBX5  exon 1 and part of intron 1 sequences but lacks inclusion of HP1α encoding exons. Inverse correlation between  STET  and HP1α coding  CBX5  mRNA expression was observed in breast cancer cell lines and tissue samples from breast cancer patients.    Conclusion  We find that HP1α is down-regulated in a mechanism involving  CBX5  promoter downstream sequences and that regulation through alternative polyadenylation and splicing generates a transcript,  STET,  with potential importance in carcinogenesis.    Electronic supplementary material  The online version of this article (doi:10.1186/s12885-016-2059-x) contains supplementary material, which is available to authorized users.

bmc cancer

Regulatory dissection of the CBX5 and hnRNPA1 bi-directional promoter in human breast cancer cells reveals novel transcript variants differentially associated with HP1α down-regulation in metastatic cells