Widespread Exaptation of L1 Transposons for Transcription Factor Binding in Breast Cancer.

Jiayue-Clara Jiang,Kyle R Upton,Joseph A Rothnagel

doi:10.3390/ijms22115625

Jiayue-Clara Jiang, Kyle R Upton + Show 1 more

Open Access

https://doi.org/10.3390/ijms22115625

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Abstract

L1 transposons occupy 17% of the human genome and are widely exapted for the regulation of human genes, particularly in breast cancer, where we have previously shown abundant cancer-specific transcription factor (TF) binding sites within the L1PA2 subfamily. In the current study, we performed a comprehensive analysis of TF binding activities in primate-specific L1 subfamilies and identified pervasive exaptation events amongst these evolutionarily related L1 transposons. By motif scanning, we predicted diverse and abundant TF binding potentials within the L1 transposons. We confirmed substantial TF binding activities in the L1 subfamilies using TF binding sites consolidated from an extensive collection of publicly available ChIP-seq datasets. Young L1 subfamilies (L1HS, L1PA2 and L1PA3) contributed abundant TF binding sites in MCF7 cells, primarily via their 5′ UTR. This is expected as the L1 5′ UTR hosts cis-regulatory elements that are crucial for L1 replication and mobilisation. Interestingly, the ancient L1 subfamilies, where 5′ truncation was common, displayed comparable TF binding capacity through their 3′ ends, suggesting an alternative exaptation mechanism in L1 transposons that was previously unnoticed. Overall, primate-specific L1 transposons were extensively exapted for TF binding in MCF7 breast cancer cells and are likely prominent genetic players modulating breast cancer transcriptional regulation.

Highlights

The normal growth and function of cells rely on the precise and coordinated expression of complex gene networks
We demonstrate that transcription factors (TF) binding in the context of breast cancer is a common feature within the L1PA2 subfamily, which contains approximately 5000 copies in the human genome [42]
We demonstrated that the L1 transposons from related evolutionary lineages were exapted to contribute substantial TF binding activities in a breast cancer model

Summary

Introduction

The normal growth and function of cells rely on the precise and coordinated expression of complex gene networks. Transcription is a primary step in gene expression and is regulated by functionally interacting transcription factors (TF), which recognise and bind specific cis-regulatory elements in genomic DNA [1,2,3]. The regulatory impacts of human TFs are highly dynamic and associated with diverse cellular functions and disease phenotypes [5]. The specific interactions between TFs and their binding sites (TFBS) throughout the genome enable the coordinated regulation of gene networks, allowing functionally associated genes to be co-expressed [6,7,8]. Transposons are repetitive DNA elements that can be hierarchically categorised into classes, families and subfamilies depending on their mode of replication, sequence structure, and evolutionary relatedness [9,11,12]. Some transposons, called the long terminal repeat (LTR) retrotransposons, originated from retroviral infections of the human cells, while the origin of the other human transposons remains largely unclear [9,13]

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