Transposable element | EPFL Graph Search

A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transposition often results in duplication of the same genetic material. In the human genome, L1 and Alu elements are two examples. Barbara McClintock's discovery of them earned her a Nobel Prize in 1983. Its importance in personalized medicine is becoming increasingly relevant, as well as gaining more attention in data analytics given the difficulty of analysis in very high dimensional spaces. Transposable elements make up a large fraction of the genome and are responsible for much of the mass of DNA in a eukaryotic cell. Although TEs are selfish genetic elements, many are important in genome function and evolution. Transposons are also very useful to researchers as a means to alter DNA inside a living organism. There are at least two classes of T

Integrative transcriptome analyses of Transposable Elements (TEs) and genes contribute to a better understanding of colorectal cancer

Eunji Shin

Cancer is the second leading cause of death worldwide. Cancer develops through multiple hallmark functions including apoptosis evasion, unlimited replicative potential, metastasis, and immune avoidance. Over the past few decades, researchers have reported a substantial amount of information about the role of gene expression dysregulation in cancer, whereas transposable elements (TEs) have been overlooked despite the fact they constitute nearly half of the human genome. TEs are DNA repetitive sequences that spread across the genome of living organisms throughout the evolution of species, contributing to genomic diversity and shaping the epigenomic landscape. The vast majority of TEs appear to be transcriptionally silent in adult tissues, thus avoiding deleterious mutational insertions and recombination events in somatic tissues. Due to the global epigenetic dysregulation that occurs during tumorigenesis, some TEs lose repressive marks and become transcriptionally active in cancer cells. Consequently, TE insertions into oncogenes and tumor suppressor genes may occur, thereby contributing to cancer development and disease progression. It is also widely accepted that some TEs harbor transcription factor recognition sites and have regulatory functions on gene expression. Some transcriptionally active TEs can give rise to alternative TE-derived chimeric gene products. Given these facts, integrative transcriptome analysis of TEs and genes may contribute to a better understanding of complex traits of cancer and help to better classify cancer subtypes with clinical implications for patients.To gain insights into the underlying mechanisms of cancer pathogenesis, we constructed a co-expression network based on the similarity in expression levels of TEs and genes. We focused on colorectal cancer (CRC), a heterogeneous disease with different genetic and molecular backgrounds, contributing to patient outcomes and response to therapy. We investigated the coordinated activity of TEs and genes in view of recurrent CRC chromosomal aberrations, genome organization, and functional significance. We further examined co-expression changes in network structure under the contrasting conditions of cancerous versus matched healthy colic mucosal tissues. We found that the cancer network was associated with a dramatic decrease in the number of gene interactions as opposed to an increase in TE interactions. Physical chromosomal distance affects the degree of co-expression, where the proximal distance effect of TE is contrasted with the distant effect of the gene. Our study sheds light on the complex interplay between TEs and genes and how they coordinately shape cancer and normal co-expression networks. Furthermore, we integrated gene and TE expression to develop a new consensus molecular subtype (CMS) classifier derived from multiple layers of TE and gene signatures. We demonstrated that our new approach led to better identification of CRC patients of the former CMS3 subtype, the most heterogeneous subtype with mixed biological characteristics, and a global reduction of the expected misclassification of other CMS subtypes. We further optimized our classifier for potential clinical use and obtained a set of 50 genes and 20 TE integrants with the best ability to identify CMS subtypes. Our integrative model could be a major add on for the development of future clinical trials by improving patient stratification over current gene-restricted molecular classifications.

EPFL2022

KRAB zinc-finger proteins and their transposable element targets: between antagonism and cooperation

Jonas Caspar De Tribolet-Hardy

There are 377 Krüppel-associated box (KRAB) domain-containing zinc finger proteins (KZFPs) in the human genome, making them the largest family of transcription factors. KZFPs are defined by a N-terminal KRAB domain and several zinc-finger domains arranged in an array at the C-terminus of the proteins. The zinc-finger domains each form sequence specific interactions with double stranded DNA, allowing the zinc-finger array to target specific genomic sequences. The KRAB domain, through its interaction with the protein TRIM28 (also known as KAP1) allows for the stable silencing of transcription in a genomic region. Together these two domains allow KZFPs to bind specific regions of the genome and generally lead to the formation of heterochromatin and silencing of transcription allthough other functions for some KZFPs have been recently reported. KZFPs usually target transposable elements (TEs), mobile genomic elements that can move through the genome either by cut-and-paste or copy-paste mechanisms and make up almost half of the human genome. Different KZFPs bind to specific regions of TEs, limiting their expression and thus mitigating some of the threat they pose to human development, allowing both the TE and its host to survive. In recent years it became apparent that both certain TEs and KZFPs have roles beyond the previously described threat and mitigation of that threat. TEs harbor gene regulatory regions allowing, through their spread, for a dissemination of those regions through the genome and for new gene regulatory networks to form. KZFPs can affect the transcription of genes located in proximity to their binding sites leading to changes in gene regulation as well. A multitude of regulatory roles involving KZFPs and TEs have been described in recent years making them an exciting field of study. A major hurdle in understanding both KZFPs and TEs is to identify the binding sites of KZFPs, as they reveal both the targets of the KZFP and how, if at all, a TE is regulated by KZFPs. To do so, we expanded on previous efforts and aimed to perform chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq) on every member of the human KZFP family. Here we present ChIP-seq experiments for 110 new KZFPs, which together with previously published data, allow us to study the binding of almost all human KZFPs (95%). The entirety of the data was analysed together to generate a coherent dataset and results for each KZFP are made available to the public on our web portal (https://tronoapps.epfl.ch/web/krabopedia/). The identified binding sites allowed us to witness the adaptation of the KZFP family to new TEs and showed how targeted sequences shift after segmental gene duplication events. Furthermore, we could corroborate that several KZFPs target the same TE subfamilies in a seemingly redundant fashion and show that unexpectedly these KZFPs arose independently in different genomic locations. These results represent a valuable tool for anyone studying KZFPs and should aid in the pursuit of both understanding KZFPs and TEs.

EPFL2022

Transposable elements contribute to the spatiotemporal microRNA landscape in human brain development

Evaristo Jose Planet Letschert, Christopher James Playfoot, Shaoline Sheppard, Didier Trono

Transposable elements (TEs) contribute to the evolution of gene regulatory networks and are dynamically expressed throughout human brain development and disease. One gene regulatory mechanism influenced by TEs is the miRNA system of post-transcriptional control. miRNA sequences frequently overlap TE loci and this miRNA expression landscape is crucial for control of gene expression in adult brain and different cellular contexts. Despite this, a thorough investigation of the spatiotemporal expression of TE-embedded miRNAs in human brain development is lacking. Here, we identify a spatiotemporally dynamic TE-embedded miRNA expression landscape between childhood and adolescent stages of human brain development. These miRNAs sometimes arise from two apposed TEs of the same subfamily, such as for L2 or MIR elements, but in the majority of cases stem from solo TEs. They give rise to in silico predicted high-confidence pre-miRNA hairpin structures, likely represent functional miRNAs and have predicted genic targets associated with neurogenesis. TE-embedded miRNA expression is distinct in the cerebellum when compared to other brain regions, as has previously been described for gene and TE expression. Furthermore, we detect expression of previously non-annotated TE-embedded miRNAs throughout human brain development, suggestive of a previously undetected miRNA control network. Together, as with non-TE-embedded miRNAs, TE-embedded sequences give rise to spatiotemporally dynamic miRNA expression networks, the implications of which for human brain development constitute extensive avenues of future experimental research. To facilitate interactive exploration of these spatiotemporal miRNA expression dynamics, we provide the "Brain miRTExplorer" web application freely accessible for the community.

2022

Integrative transcriptome analyses of Transposable Elements (TEs) and genes contribute to a better understanding of colorectal cancer

Eunji Shin

EPFL2022

Transposable elements contribute to the spatiotemporal microRNA landscape in human brain development

Evaristo Jose Planet Letschert, Christopher James Playfoot, Shaoline Sheppard, Didier Trono

2022

KRAB zinc-finger proteins and their transposable element targets: between antagonism and cooperation

Jonas Caspar De Tribolet-Hardy

EPFL2022