Computational and functional annotation of genomic elements during development of the model vertebrate zebrafish

Project Information

ZENCODE-ITN

Grant agreement ID: 643062

DOI 10.3030/643062

Project closed

EC signature date 18 December 2014

Start date 1 January 2015

End date 31 December 2018

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost € 3 724 035,89

EU contribution € 3 724 035,89

Coordinated by

THE UNIVERSITY OF BIRMINGHAM
United Kingdom

Periodic Reporting for period 2 - ZENCODE-ITN (Computational and functional annotation of genomic elements during development of the model vertebrate zebrafish)

Reporting period: 2017-01-01 to 2018-12-31

Summary of the context and overall objectives of the project

The recent explosion of next generation sequencing (NGS) data has led to a critical shortage of computational biology expertise. As NGS methods are expected to become pervasive from basic science to personalised medicine there is an urgent need for highly skilled young scientists trained in both computational biology and experimental wet lab biology. Our network addresses this important problem of the postgenomic era. We aim to provide multi-disciplinary skills for a solid foundation in computational biology and developmental genomics. Developmental genomics is central to understanding of ontogeny and many genetic and congenital anomalies, but was outside the scope of the landmark ENCODE project. ENCODE highlighted the need for an in vivo vertebrate model that enables high throughput in vivo functional testing of hypotheses generated from genome scale annotation. Zebrafish is an ideal model for extending the scope of genomics to vertebrate development with high throughout capabilities. We aim to comprehensively annotate functional elements, decipher genomic codes of transcription, as well as coding and non-coding gene function during development and enhance zebrafish as an attractive developmental, comparative and disease model. The participants include SMEs, major zebrafish genomics laboratories, eminent computational biologists and world-class genomics technology experts active in FANTOM and ENCODE.
In our programme we have created an unique compendium of zebrafish genomics database and resource which consists of new genomics data generated by the network partner laboratories and collation of most of the available published data meticulously assembled and re-analysed by standardised pipelines by network partners. From the new data we were able to deduce novel biological observations for example on the genetic basis of endoderm and primordial germ cell specification, functional genetics of muscle development and nuclear and chromosomal topology organisation during development of a vertebrate animal model. The generation of the zebrafish genomics resource led by ZENCODE-ITN partners encompassed a larger global network of collaborators beyond ZENCODE-ITN, and called DANIO-CODE. ZENCODE-ITN partners played crucial roles in creating to a publicly accessible DANIO-CODE data coordination centre and a searchable genomics resource for both zebrafish model users and the wider genomics community.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the last four years the ZENCODE-ITN project has fulfilled its key objectives in recruitment and training of 15 early stage researchers, setting up and utilising network communication channels, a website and student network via social media. The progress and results of the network activities were communicated via two international conferences, presentations at independent scientific meetings and peer reviewed publications. All due deliverables have been submitted and expected milestones completed. Seven successful training events have been organised including several mastercourses and transferable skills training events.

We have made substantial progress in the following scientific objectives:
Computational tools development:
- new data mining tool is in development for analysing in which tissues and when during development genes work
- we established a Data Coordination Centre (DCC) for collecting and standardizing zebrafish epigenome, transcriptome datasets,
- Software and data structures for anatomy specific gene expression analysis has been developed
- Computational pipeline has been created to compare spatio-temporal expression profiles and to identify co-expression groups
- genomics data visualisation tools have been developed for visualising multidimensional datasets

Experimental technology development and data collection:
- We have collected genome wide epigenetic data from a variety of tissues and cell types including primordial germ cells, pancreatic cell types, endoderm, muscle and nervous system
- We have developed new miniaturized biochemical techniques to collect genome wide data from small cell numbers (e.g. chromatin immunoprecipitation, promoter capture technology- CAGE and chromosome conformation capture assay)
- We have collected human non-coding functional elements for pancreatic islets to then study their function in a fish embryo model

Genome wide data annotation:
- ZENCODE-ITN partners progressed substantially with the comprehensive annotation of the zebrafish genome by seeding and leading the efforts of a global consortium effort under the umbrella of DANIO-CODE.
- ZENCODE-ITN members have played central and dominant role in initiating, establishing, coordinating managing and undertaking DANIO-CODE objectives (http://www.birmingham.ac.uk/generic/danio-code/data-coordination-centre.aspx)
- We have generated a catalog and classification of so called non-coding RNAs in nuclear and cytoplasmic fractions of developing embryos at various stages
- We have analysed sequence variants of human disease associated non-coding DNA elements which are predicted to regulate gene activity
- We have characterised the epigenetic landscape of primordial germ cells and identified key
- We have characterised transcription regulatory networks in endoderm development and pancreatic islet specification
- We have characterised zebrafish mutants affecting muscle development
by transcriptome analysis

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

By training our 15 ESRs in various genomics and epigenomics techniques as well as in developing and using advanced algorithms with multidimensional data analysis and visualisation we have educated drivers of new development in genomics and its downstream applications like personalised medicine.
Our DANIO-CODE portal allows easy access to processed zebrafish genomic and epigenomic data to wider scientific community and in this way will strengthen zebrafish as model organism for development.
Our efforts will have considerable impact on expansion of the use of zebrafish as genomics model and the generated public database of zebrafish genomics datasets will be a resource for the over thousand of zebrafish user laboratories and the even larger broader genomics community.

Dissemination:
Two international genomic conference were organized (see website https://zencode-itn.eu/conferences). At these meetings, all ZENCODE students presented the results of their work and had the opportunity to discuss with scientists expert in the genomic field.
Several peer reviewed publications resulted from the ZENCODE –ITN Project acknowledging the support of the ITN programme. A website was established https://zencode-itn.eu/; and also http://www.birmingham.ac.uk/generic/zencode-itn/index.aspx ). A twitter account was also developed to increase information exchange (https://twitter.com/zencodeitn). The ZENCODE-ITN students designed and produced an explainer video accessible at https://zencode-itn.eu/outreach.html and https://www.youtube.com/watch?v=antNReIh5VU.

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