Integrated transcription factor profiling with transcriptome analysis: identification of L1PA2 transposons as global regulatory modulators in a breast cancer model

Jiayue-Clara Jiang⁰, Joe Rothnagel⁰, Kyle Upton⁰
(0) The University of Queensland

Find me on Wed Nov 25th, 1:30-2:50pm AEDT in Remo, table 12

Abstract
LINE1 retrotransposons occupy approximately 17% of the human genome. Many LINE1 retrotransposons contain cis-regulatory sequences, such as transcription factor binding sites and promoters, which can be exapted to modulate human gene expression. While transposons are generally silenced in somatic tissues, many LINE1 retrotransposons can escape epigenetic repression in epithelial cancers, become transcriptionally active and contribute regulatory activity. We have developed a bioinformatic pipeline for the integrated analysis of transcription factor binding and transcriptomic data to identify transposon-derived promoters that are activated in specific diseases and developmental states. We applied this pipeline to a breast cancer model, and showed that L1PA2 retrotransposons, a primate-specific subfamily of LINE1, contribute abundant regulatory sequences to co-ordinated transcriptional regulation in breast cancer. Analysis of ChIP-seq data showed that 27% of L1PA2 retrotransposons were bound by transcription factors in MCF7 cells, with the majority of binding sites clustering in the 5’ untranslated region. L1PA2 retrotransposons also facilitated binding site co-localisation of functionally interacting transcription factors, many of which are known to be involved in the transcriptional mis-regulation in cancer. In addition to being a rich reservoir of oncogenic transcription factor binding sites, L1PA2 retrotransposons also contributed transcription start sites to a number of transcripts in MCF7 cells, suggesting the activation of dormant promoters. These transcripts showed upregulated expression in MCF7 cells compared to the near-normal MCF10A cells, and their cancer-specific expression was supported by an active epigenetic profile. Our results demonstrate that L1PA2 retrotransposons are a prominent contributor of transcription factor binding sites in breast cancer, and drive the expression of cancer-specific transcripts through co-ordinated binding of oncogenic transcription factors. Understanding the regulatory impact of L1PA2 on breast cancer genomes may provide an insight into cancer genome regulation, and provide novel biomarkers for disease diagnosis and novel candidates for targeted therapy.