Developmental Epigenomics

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

Our cells need to express the right set of genes at the right time (e.g., during development), and in the right cells (e.g., white-blood cells fighting an infection). Your genes are part of the 2 metres of DNA that make up your genome, which has to be stored inside a cell nucleus only a few microns across. This is a tremendous level of compaction, equivalent to fitting the length of the M25 motorway inside your fridge.
The cell has molecular mechanisms that determine the correct folding and packaging of the DNA inside the nucleus. When these fail, this leads to numerous developmental disorders and diseases such as cancer. Therefore, understanding these molecular mechanisms is of great importance.
We use a combination of genomic and computational techniques to examine the mechanisms that control the organisation of the DNA in the nucleus, and, in particular, how these work during early embryonic development. We study early embryonic development, in a range of model organisms, since this is a time window where cell differentiation programmes need to be established for the correct development of an individual. In addition, we also examine the differentiation of mature gametes since the correct specification of these cells is fundamental for fertility. Tracking these changes allows us to discover key molecular mechanisms that are important for healthy development and understand how these are affected in human disease.

Technical Summary

The three-dimensional organisation of chromatin in the nucleus plays a fundamental role in providing cells with correct gene expression control throughout development and normal physiology. Recent advances in our ability to quantitatively measure chromatin conformation, such as Hi-C, have provided invaluable insight into how a multi-layered structure of compartments, globular domains and loops neatly arranges interphase chromatin according to its function. The three-dimensional organisation of the genome is intimately intertwined with additional molecular mechanisms that control gene expression, such as DNA methylation and chromatin modifications, among others. Highlighting the importance of this organisation for healthy genome function, mutations in elements that determine chromatin conformation result in severe developmental disorders and cancer. Since chromatin organisation lies at the most basic layer of genome regulation, it is paramount to understand the molecular mechanisms that drive this organisation.
We employ genomic techniques that examine changes in all these different epigenetic features (e.g., chromatin organisation, DNA methylation, chromatin modifications) during early embryonic development in a range of model organisms. Gametogenesis and early embryonic development are key stages in the life of an organism, since the epigenetic programmes of the fully differentiated gametes need to be reverted back to a totipotent stage, in order to give rise to a new individual. By examining changes in chromatin conformation at these key developmental points genome-wide, we can identify the molecular mechanisms that drive these changes, and as a result, decipher how these are affected in disease.
We pay particular emphasis to repetitive elements, since these display a strong association with molecular features characteristic of early embryonic developmental processes. Specifically, families of murine-specific retrotransposons, such as MERVL, seem to play a key role during zygotic genome activation, i.e., the key stage when the zygotic genome takes over developmental control from the maternal contributed products present in the oocyte. Through careful computational analysis of these elements, we aim to understand how these retroviral-derived repetitive elements have evolved to acquire their own bona-fide regulatory activities in the genome.
Overall, our research aims to discover key molecular mechanisms that determine the correct establishment of gene developmental programmes in the early embryo and to characterise how these are affected in human disease.
 
Description AMS Professorship Award for Professor Juan Vaquerizas, Imperial College London
Amount £500,000 (GBP)
Funding ID APR3\1017 
Organisation Academy of Medical Sciences (AMS) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2021 
End 01/2024
 
Description La Caixa Foundation
Amount £50,000 (GBP)
Organisation La Caixa Banking Foundation 
Sector Private
Country Spain
Start 10/2020 
End 09/2022
 
Title CHESS 
Description CHESS is a tool for the comparison and automatic feature extraction for chromatin contact data 
Type Of Material Data analysis technique 
Year Produced 2020 
Provided To Others? Yes  
Impact Galan S, Machnik N, Kruse K, Díaz N, Marti-Renom MA, Vaquerizas JM. (2020). CHESS enables quantitative comparison of chromatin contact data and automatic feature extraction.. Nature genetics, 52 (11), pp. 1247-1255 
URL https://github.com/vaquerizaslab/chess
 
Title Dorsoventral patterning 3D genome 
Description Hi-C, Micro-C, single-cell RNA-seq and ChIP-seq of Drosophila embryos to investigate chromatin state during dorsal-ventral patterning. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact Ing-Simmons E, Vaid R, Mannervik M, Vaquerizas J. (2020). Independence of 3D chromatin conformation and gene regulation during Drosophila dorsoventral patterning. 
URL https://github.com/vaquerizaslab/Ing-Simmons_et_al_dorsoventral_3D_genome
 
Title FAN-C 
Description An easy-to-use command-line tool and powerful Python API with a broad feature set covering matrix generation, analysis, and visualisation for chromatin conformation-like data. 
Type Of Material Data analysis technique 
Year Produced 2020 
Provided To Others? Yes  
Impact Kruse K, Hug CB, Vaquerizas JM. (2020). FAN-C: a feature-rich framework for the analysis and visualisation of chromosome conformation capture data.. Genome biology, 21 (1), pp. 303 
URL https://github.com/vaquerizaslab/fanc
 
Description Analysis of heterochromatin in pericentromeric regions 
Organisation Helmholtz Zentrum München
Country Germany 
Sector Academic/University 
PI Contribution Analysed chromatin marks and gene expression data for early embryonic mouse cells. Contributed to the writing of the resulting manuscript.
Collaborator Contribution The partners designed the experiments, generated the datasets and help in the interpretation of the results and the drafting of the resulting publication.
Impact Burton A, Brochard V, Galan C, Ruiz-Morales ER, Rovira Q, Rodriguez-Terrones D, Kruse K... Torres-Padilla ME. (2020). Heterochromatin establishment during early mammalian development is regulated by pericentromeric RNA and characterized by non-repressive H3K9me3.. Nature cell biology, 22 (7), pp. 767-778
Start Year 2017
 
Description CHESS development 
Organisation Centre for Genomic Regulation (CRG)
Country Spain 
Sector Academic/University 
PI Contribution We designed the entire software, benchmarked it and test it against several chromatin conformation datasets.
Collaborator Contribution The partners contributed an implementation of an algorithm able to select specific regions of interest in the datasets.
Impact Galan S, Machnik N, Kruse K, Díaz N, Marti-Renom MA, Vaquerizas JM. (2020). CHESS enables quantitative comparison of chromatin contact data and automatic feature extraction.. Nature genetics, 52 (11), pp. 1247-1255
Start Year 2019
 
Description Cohesin/Polycomb degron 
Organisation University of Oxford
Department Department of Biochemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated and analysed chromatin conformation data for mouse embryonic stem cells upon perturbation of different 3D genome regulators.
Collaborator Contribution Our partners have provided cell lines, experimental design and critical analysis of the resulting datasets, as well as additional follow up experiments.
Impact Rhodes JDP, Feldmann A, Hernández-Rodríguez B, Díaz N, Brown JM, Fursova NA, Blackledge NP... Klose RJ. (2020). Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells.. Cell reports, 30 (3), pp. 820-835.e10
Start Year 2019
 
Description Transcriptional analysis of zebrafish germ cells 
Organisation University of Birmingham
Department College of Medical and Dental Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysed transcriptomics data for zebrafish germ cells.
Collaborator Contribution Experimental design, data production and data integration.
Impact Germ plasm localisation dynamics mark distinct phases of transcriptional and post-transcriptional regulation control in primordial germ cells View ORCID ProfileFabio M. D'Orazio, Piotr Balwierz, Yixuan Guo, Benjamín Hernández-Rodríguez, Aleksandra Jasiulewicz, View ORCID ProfileJuan M. Vaquerizas, Bradley Cairns, Boris Lenhard, Ferenc Müller doi: https://doi.org/10.1101/2020.01.12.903336
Start Year 2015
 
Title CHESS 
Description CHESS is a tool for the comparison and automatic feature extraction for chromatin contact data 
Type Of Technology Webtool/Application 
Year Produced 2020 
Open Source License? Yes  
Impact No notable impacts. 
URL https://github.com/vaquerizaslab/chess
 
Title FAN-C: A Feature-rich Framework for the Analysis and Visualisation of Chromosome Conformation Capture Data 
Description Chromosome conformation capture data, particularly from high-throughput approaches such as Hi-C, are typically very complex to analyse. Existing analysis tools are often single-purpose, or limited in compatibility to a small number of data formats, frequently making Hi-C analyses tedious and time-consuming. Here, we present FAN-C, an easy-to-use command-line tool and powerful Python API with a broad feature set covering matrix generation, analysis, and visualisation for C-like data (https://github.com/vaquerizaslab/fanc). Due to its compatibility with the most prevalent Hi-C storage formats, FAN-C can be used in combination with a large number of existing analysis tools, thus greatly simplifying Hi-C matrix analysis. 
Type Of Technology Software 
Year Produced 2020 
Impact This tool has greatly simplified the analysis of chromatin conformation data. 
URL https://zenodo.org/record/3984771
 
Title vaquerizaslab/Ing-Simmons_et_al_dorsoventral_3D_genome: Release for paper 
Description Added explanations and some missing code 
Type Of Technology Software 
Year Produced 2021 
Open Source License? Yes  
Impact No notable impacts. 
URL https://zenodo.org/record/4542753
 
Description Women in science awareness day 2020 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Twitter campaign to raise awareness of female role models as part of the international women in science day.
Year(s) Of Engagement Activity 2020
URL https://twitter.com/vaquerizas_lab/status/1236702499488387074
 
Description Women in science awareness day 2021 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A one-month Twitter campaign designed to increase awareness of women in science by individually portraying in individual tweets the profiles of female researchers in the team.
Year(s) Of Engagement Activity 2021
URL https://twitter.com/vaquerizas_lab/status/1359854488539058178