Génome | EPFL Graph Search

Le génome (//), ou plus rarement génôme, est l'ensemble du matériel génétique d'une espèce codé dans son acide désoxyribonucléique (ADN), à l'exception de certains virus dont le génome est constitué d'acide ribonucléique (ARN). Il contient en particulier tous les gènes codant des protéines ou correspondant à des ARN structurés. Il se décompose donc en séquences codantes (transcrites en ARN messagers et traduites en protéines) et non codantes (non transcrites, ou transcrites en ARN, mais non traduites). Le génome est constitué de un ou plusieurs chromosomes dont le nombre total dépend de l'espèce considérée, chaque chromosome étant constitué d'une unique molécule d'ADN, linéaire chez les eucaryotes et le plus souvent circulaire chez les procaryotes. Chaque chromosome peut être présent en un ou plusieurs exemplaires, le plus souvent deux chez les espèces sexuées, l'un d'origine maternelle et l'autre d'origine paternelle (organisme diploïde). La science qui étudie le génome est la géno

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

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

Improving Comparative Genomic Studies

Cristina Gabriela Ghiurcuta

Comparative genomics aims to understand the structure of genomes and the function of various genomic fragments, by transferring knowledge gained from well studied genomes, to the new object of study. Rapid and inexpensive high-throughput sequencing is making available more and more complete genome sequences. Despite the significant scientific advance, we still lack good models for the evolution of the genomic architecture, therefore analyzing these genomes presents formidable challenges. Early approaches used pairwise comparisons, but today researchers are attempting to leverage the larger potential of multiway comparisons. Current approaches are based on the identification of so called syntenic blocks: blocks of sequence that exhibit conserved features across the genomes under study. Syntenic blocks are in many ways analogous to genesâ -in many cases, the markers are used to constructing them are genes. Like genes they can exist in multiple copies, in which case we could define analogs of orthology and paralogy. However, whereas genes are studied at the sequence level, syntenic blocks are too large for that level of detail - it is their structure and function as a unit that makes them valuable for genome level comparative studies. Syntenic blocks are required for complex computations to scale to the billions of nucleotides present in many genomes; they enable comparisons across broad ranges of genomes because they filter outmuch of the individual variability; they highlight candidate regions for in-depth studies; and they facilitate whole-genome comparisons through visualization tools. The identification of such blocks is the first step in comparative studies, yet its effect on final results has not been well studied, nor has any formalization of syntenic blocks been proposed. Tools for the identification of syntenic blocks yield quite different results, thereby preventing a systematic assessment of the next steps in an analysis. Current tools do not include measurable quality objectives and thus cannot be benchmarked against themselves. Comparisons among tools have also been neglected - what few results are given use superficial measures unrelated to quality or consistency. In this thesis we address two major challenges, and present: (i) a theoretical model as well as an experimental basis for comparing syntenic blocks and thus also for improving the design of tools for the identification of syntenic blocks; (ii) a prototype model that serves as a basis for implementing effective synteny mining tools. We offer an overview of the milestones present in literature, on the development of concepts and tool related to synteny; we illustrate the application of the model and the measures by applying them to syntenic blocks produced by different contemporary tools on publicly available data sets. We have taken the first step towards a formal approach to the construction of syntenic blocks by developing a simple quality criterion based on sound evolutionary principles. Our experiments demonstrate widely divergent results among these tools, throwing into question the robustness of the basic approach in comparative genomics. Our findings highlight the need for a well founded, systematic approach to the decomposition of genomes into syntenic blocks and motivate the second part of the work - starting from the proposed model, we extend the concept with data dependent features and constraints, in order to test the concept on cases of interest.

EPFL2014

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

Jonas Caspar De Tribolet-Hardy

EPFL2022

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

Eunji Shin

EPFL2022

Improving Comparative Genomic Studies

Cristina Gabriela Ghiurcuta

EPFL2014