1st CERCA Conference

April 28th, 2014

Big Projects for CERCA Institutes

M. Beato

CRG

STRATEGIC PARTNERSHIPS initiated by the CRG

EU-LIFE

European Life Sciences Institutes for Excellence

13 partners across Europe

• Promoting excellence • Integration

• Attract talent, support mobility • Sharing best practise in research

and management

CORE FOR LIFE

Excellence Alliance of Life Sciences Core Facilities in Europe

7 partners across Europe

• Sharing best practice • Training

• Scouting new technologies • Capacity sharing

• EU Funding

INTERNATIONAL “BIG″ PROJECTS

ICGC

Genome sequencing of chronic

lymphocytic leukemia (CLL)

IHEC

A BLUEPRINT of Haematopoietic

Epigenomes (FP7)

ENCODE

The Encyclopedia Of DNA Elements (NIH-funded)

GTEx

Genotype-tissue Expression Portal

(NIH funded)

FANTOM

Functional annotation of the mammalian

genome

THE EGA European Genome-phenome Archive

A service for permanent archiving and secure sharing of personally identifiable genetic and phenotypic data from biomedical research projects.

• A key resource for personalized systems medicine.

•

• EBI-CRG-BSC partnership to host, manage and improve the EGA.

EMBL

EBI

GENES

• Genetic diseases

• Pre-natal screening

PROTEINS

• Drug targets

• Signalling pathways

CELLS

• Disease mechanisms

• Stem cells

• Networks

TISSUES

• Tumors

• Wound Healing

• Regeneration

• Tissue Engineering

Multicellular Systems Biology:

taking us to higher levels of complexity

A new EMBL OUTSTATION at the CRG

GENES

• Genetic diseases

• Pre-natal screening

PROTEINS

• Drug targets

• Signalling pathways

CELLS

• Disease mechanisms

• Stem cells

• Networks

TISSUES

• Tumors

• Wound Healing

• Regeneration

• Tissue Engineering

Multicellular Systems Biology:

taking us to higher levels of complexity

3D / 4D Mesoscopic Imaging

Modelling Multicellular Processes

A new EMBL OUTSTATION at the CRG

EUROPEAN COORDINATED PROJECTS

4DCellFate

Global understanding of the PRC and NuRD

complexes in stem cells and disease.

SysteMTb

Systems Biology of M. tuberculosis and its

interaction with the host.

SWARMORGAN

Theoretical framework for swarms of GRN-controlled agents in morphogenesis

and robotics.

BioPreDyn

New systems biology and bioinformatics tools for

biotechnology applications.

FLiACT

Systems neuroscience in Drosophila (training

network).

Bioinformatics and Genomics

R.GUIGÓ

AdG 2011

(2.1 M€, 2012-2017)

G.TARTAGLIA StG 2012

(1.5 M€, 2013-2017)

T.GABALDÓN

ICREA – StG 2012

(1.3 M €, 2013-2017)

F.KONDRASHOV

ICREA - StG 2013

(1.5 M€, 2014-2018)

Nearly half of the PIs hold an ERC grant!

Total funding current grants: 30.5 M€ / 13 grants

Cell and Dev. Biology

M.MENDOZA

StG 2010

(1.1 M€, 2011-2016)

V.MALHOTRA

ICREA – AdG 2010

(2.2M€, 2011-2016)

P.CARVALHO

StG 2012

(1.5 M€, 2013-2018)

L.SERRANO

ICREA - AdG 2008

(2.4 M€, 2013-2015)

PoC 2012

(0.15 M€, 2009-2015)

Systems Biology

B.LEHNER

ICREA – StG 2007

(1.1 M€, 2008-2014, )

CoG 2013

(2 M€, 2014-2019)

Gene Regulation, Stem Cells & Cancer

P.COSMA

ICREA – StG 2009

(1.6 m€, 2010-2015)

M.BEATO

T.GRAF (ICREA)

M.MARTÍ-RENOM

(ICREA, CNAG-CRG)

G.FILION

SyG 2013 4D genome

(12.3 M€, 2014-2018)

+ 1 StG (M. Isalan)

to Imperial College (UK) in 2013 + 1 StG (H.López-Schier)

to Helmholtz (DE) in 2012

+ 1 StG (S. Aznar-Benitah)

to IRB Barcelona (ES) in 2013

ERC Principal Investigators - CRG

4DGenome

Dynamics of human genome architecture

in stable and transient gene expression changes

Miguel Beato, CRG, Molecular Cell Biology

Thomas Graf, CRG, Stem Cell Biology

Guillaume Filion, CRG, Statistical Biology

Marc Marti-Renom, CNAG-CRG, Structural Biology

The logic

Function Protein

Sequence

Function

Human

Genome

Sequence

Function

Genome structure & dynamics will help to understand why the cells of our

body are so different although they share the same genetic information

Function

Function

Gene Networks Different cell types have different sets of transcription factors,

which act on cell-specific enhancers and establish different gene networks

Is there a structural substrate for the cell-specific gene networks?

Do temporal changes in the genome 3D structure

contribute to gene regulation?

Core support

Sequencing

Computing 8 Illumina HiSeq2000

2 Illumina HiSeq2500

1 MiSeq

2.2 Pb of storage space

950 core cluster supercomputer

10x10 Gb/s connection to BSC

Genomics

Proteomics

FACS

High resolution Imaging STED,

Two photon Confocal,

TIRF, FLI, FCS

Support from other CERCA centers

MareNostrum (29th)

1,1 Petaflops

48,896 Intel processors

100.8 TB of memory

2 PB of disk storage.

NIKON Center of Excellence in STORM

Deconvolution and NIS-Elements C with N-

STORM Analysis.

4DGenome Team Dynamics

Unique

Model systems

Marc A. Marti-Renom

Thomas Graf Guillaume Filion

Miguel Beato

Model system I (T. Graf):

Stable Cell Reprogramming

3 days

Uninduced

B-cells

Induced

Macrophages

C/EBPα

100% conversion

committed after 24 h

Does the 3D genome structure instruct cell reprogramming?

Model system II. T47D Breast Cancer Cells Rapid regulation of thousands of genes by hormones

Do changes in 3D genome structure precede changes in gene expression?

1 h 6 h

108

98

689

381 1530

90

645

43

-5

-2

-1

0

1

2

5

Objectives

at high resolution changes in the 3D genome organization during stable

trans-differentiation and transient hormonal response.

multi-dimensional and multi-scale data analysis, integration & visualization.

mechanisms that establish, maintain and alter the 3D genome organization.

relationship between the 3D organization of the genome, epigenetic

marks and transcription.

Describe

Integrate and Visualize

Discover

Perturb and Validate

Genome Structure: TADs

Single cell based analysis using Light microscopy

Population based analysis by Chromosome Conformation Capture

Adapted from Nora, E. P., Dekker, J. & Heard, E. BioEssays (2013)

crosslink cut ligate

clean DNA

sequence

Hi-C

All levels of genome organization

Adapted from Nora, E. P., Dekker, J. & Heard, E. BioEssays (2013)

Single cell based analysis using Light microscopy

Population based analysis by Chromosome Conformation Capture

Nanoscopy should allow to see the chromatin fiber

High resolution microscopy (Nanoscopy)

2 μm 2 μm

0.5 μm 0.5 μm

Confocal STED

Collaboration with Melike Lakadamyali

ERC Starting Grant- ICFO

1D track

Exp. Info

3D structure

2D tracks “Radar”

alpha 3D genome browser

4DGenome - Impact

• Open access to:

- Large scale datasets of unprecedented resolution and usability

- Software for data quality control and visualization including a 3D browser

• A new paradigm to understand human gene regulation:

How the 3D genome structure conditions cell-specific interactions of

regulatory sequences with target genes

• Discovering organizing principles for engineering the human genome.

Basic science

• 3D reorganization will help understanding disease and aging

• 3D genome structure conditions chromosomal translocation and in cancer

Health relevance

Contributions to the science community

THANKS!