Organització 3D de la cromatina

  • Javierre Lab 2021
ICO - German Trias i Pujol

IJC Building, Campus ICO-Germans Trias i Pujol
Ctra de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona, Spain

Tel: (+34) 935 572 800 extn 4160 

Webpage javierreLab.com  @JavierreLab

 

Directions

Summary

Genetics and epigenetics of normal and malignant haematopoiesis in space and time

We are a group of passionate scientists with an insatiable thirst for learning about spatiotemporal architecture of the genome and its role in cell differentiation and function in health and disease. Our group combines cutting-edge experimental and bioinformatics approaches to understand the dynamic and specific 3D chromatin organization of normal and malignant haematopoiesis and its interaction with non-coding determinants and trans-regulatory elements. Our long-term goal is to keep making progress in the fight against cancer. We will not stop until a cure is found.

Research

Enhancers are critical modulators of gene transcription through physical interactions with target promoters that often locate distally in the genome. The physical proximity between enhancers and promoters is ultimately enabled and determined by the three-dimensional folding of the chromatin within the nucleus. Although enhancers can be defined through well-characterized features, predicting their target genes at distal location remains challenging due to the high complexity of studying enhancer-promoter interactions, and the large variability according to cell-type and state. This gap of knowledge is particularly problematic for understanding the molecular mechanisms associated to inherited and de novo acquired mutations and epimutations involved in common human diseases, which are all highly enriched at regulatory elements 

To overcome these critical limitations, we have recently developed a low input cost-effective method to robustly map and compare promoter interactomes at high resolution in rare cell populations previously unmeasurable. This new method broadens the capacity for studying organism developments, in vivo cell commitment, cellular response to a wide range of external stimulus and disease pathogenesis.

Our goals

Our lab’s main research goals, which are motivated by this gap in the knowledge, are as follows:

1. To define the cell type-specific 3D chromatin organization in human haematopoietic cells. Human haematopoietic differentiation dogma is currently a subject of debate. All blood cells originate from haematopoietic stem cells (HSCs), which represent the apex of a differentiation cascade of progenitor cell types that gives rise to billions of new differentiated cells every day. HSC differentiation, which progresses through stepwise hierarchical restriction of lineage potential, has been extensively characterized at epigenetic, transcriptional and functional levels. However, the contribution of genome architecture in regulating haematopoiesis remains unexplored.

Motivated by this gap of knowledge, we aim to investigate whether the dynamic changes in chromatin interactions between gene promoters and regulatory elements can shape transcription decisions controlling haematopoiesis and blood cell function. These insights can lead to improvements in regenerative medicine strategies, especially bone marrow transplants, which represent one of the most promising approaches to treating many diseases, including blood cancer.

2. To identify the altered DNA topology in blood cancer. The genome architecture plays a key role in genome expression regulation and DNA repair. Chromatin interactions are therefore crucial for cellular health, and errors in these interactions can give rise to the development of a broad range of diseases, including blood cancer. Research into these altered 3D structures can help improve knowledge of the tumour process, thereby providing new opportunities for the development of novel treatment approaches and diagnostic strategies.

3. To prioritize new candidate genes and pathways related to leukemias and lymphomas. During the previous years, thousands of determinants associated with blood cancer have been identified. However, most of them remains unexplored because of these target non-coding regions, frequently enhancers and other distal regulatory elements. Genetic and epigenetic alterations at distal regulatory elements have the potential to alter the regulatory properties and ultimately lead to quantitative changes in expression of distal target genes with pathological outcome. However, in most of the cases, the target genes area unknown. By studying the physical interactions between gene promoters and regulatory elements, we connect blood cancer cis and trans determinants to putative target genes, thereby prioritizing new candidate genes and pathways and offering an insight into the genomic regulatory mechanisms underlying cancer. In addition, the interpretation of the non-coding regions altered in disease will also help us improve patient outcome prediction and allow us to design better, more personalized treatments.

Our challenges:

Through our research, we hope to answer the following questions:

- Can the dynamic changes in chromatin interactions shape the transcription decisions controlling haematopoiesis and blood cell function?

- Which are the blood cell-type specific key factors orchestrating genome architecture?

- How does the altered genome architecture drive malignant transformation?

- What is the role of non-coding determinants in cancer predisposition, development and relapse?

Why our research matters

Blood cancers, including leukemias and lymphomas, are a leading cause of mortality in paediatric and adult patients worldwide. We aim to provided fundamental understanding of blood cancer development and relapse to identify new biomarkers and novel therapeutic targets to ultimately improve patient survival.

Keywords

Genome architecture, spatial-temporal chromatin organization, haematopoiesis, blood cancer, cis non-coding determinants, enhancer-promoter interactions

Social media

- ORCID: http//orcid.org/0000-0002-8682-6748 

- ResearcherID: A-2974-2017

- Website of the 3D Chromatin Organization Research Group:

 https://www.javierrelab.com/

- Twitter: @JavierreLab @BiolaMJavierre

- ResearchGate: https://www.researchgate.net/profile/Biola_Javierre

Awards

 

 

2019 Top 10 Female Scientific Leaders in Spain and Top 100 Female Leaders in Spain Awards, Mujeres&Cia Foundation, which identifies the 10 best female scientists and the 100 best female leaders in Spain. 

2019 L'Oréal-UNESCO International Rising Talents Award 2019, which recognizes the 15 most promising young female scientists worldwide from four disciplines (Life Sciences, Physical Sciences, Engineering and Formal Sciences). 

2019-2022 Plan Nacional Grant (RTI2018-094788-A-I00).

2019-2022 La Caixa Junior Leader Fellowship. 2019-2022 Deutsche Leukämie-Stiftung Grant, in collaboration with Björ Chapuy (Dana-Farber Cancer Institute / Harvard Medical School, USA, and University Medical Centre Göttingen, Germany).

2018 L'Oréal-UNESCO For Women in Science Research Award, L'Oréal Foundation, Spain. 

2018-2023 Ramón y Cajal Fellowship (RYC-2016-19665), Spanish Ministry of Science, Innovation and University. The Spanish Ramón y Cajal Programme recruits outstanding researchers for R&D centres on five-year contracts through a highly competitive process to select candidates based on scientific excellence criteria. 

2017 LIBRA Career Development Compass fellowship for female scientists. LIBRA is a Coordination and Support Action project of the European Commission’s Horizon 2020 framework programme. 

People

Selected publications

Watt S., Vasquez L., Walter K, Mann AL, Kundu K, Chen L, Yan Y, Ecker S, Burden F, Farrow S, Farr B, Lotchkova V, Elding H, Mead D, Tardaguila M, Ponstingl H, Richardson D, Datta A, Flicek P, Clarke L, Downes K, Pastinen T, Fraser P, Frontini M, Javierre BM, Spivakov M, Soranzo N

Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility

Nat Commun (Under revision) 2020, .
Neutrophils play fundamental roles in innate inflammatory response, shape adaptive immunity1, and have been identified as a potentially causal cell type underpinning genetic associations with immune system traits and diseases2,3 The majority of these variants are non-coding and the underlying mechanisms are not fully understood. Here, we profiled the binding of one of the principal myeloid transcriptional regulators, PU.1, in primary neutrophils across nearly a hundred volunteers, and elucidate the coordinated genetic effects of PU.1 binding variation, local chromatin state, promoter-enhancer interactions, and gene expression. We show that PU.1 binding and the associated chain of molecular changes underlie genetically-driven differences in cell count and autoimmune disease susceptibility. Our results advance interpretation for genetic loci associated with neutrophil biology and immune disease.
Azagra A, Marina-Zárate E, Ramiro AR, Javierre BM, Parra M

From Loops to Looks: Transcription Factors and Chromatin Organization Shaping Terminal B Cell Differentiation.

Trends Immunol. 7 Des 2019, . Epub 7 Des 2019
B lymphopoiesis is tightly regulated at the level of gene transcription. In recent years, investigators have shed light on the transcription factor networks and the epigenetic machinery involved at all differentiation steps of mammalian B cell development. During terminal differentiation, B cells undergo dramatic changes in gene transcriptional programs to generate germinal center B cells, plasma cells and memory B cells. Recent evidence indicates that mature B cell formation involves an essential contribution from 3D chromatin conformations through its interplay with transcription factors and epigenetic machinery. Here, we provide an up-to-date overview of the coordination between transcription factors, epigenetic changes, and chromatin architecture during terminal B cell differentiation, focusing on recent discoveries and technical advances for studying 3D chromatin structures.
Més informació
Siersbæk R, Madsen JGS, Javierre BM, Nielsen R, Bagge EK, Cairns J, Wingett SW, Traynor S, Spivakov M, Fraser P, Mandrup S

Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation.

Mol. Cell 4 Mai 2017, 66 (3) 420-435.e5.
Interactions between transcriptional promoters and their distal regulatory elements play an important role in transcriptional regulation; however, the extent to which these interactions are subject to rapid modulations in response to signals is unknown. Here, we use promoter capture Hi-C to demonstrate a rapid reorganization of promoter-anchored chromatin loops within 4 hr after inducing differentiation of 3T3-L1 preadipocytes. The establishment of new promoter-enhancer loops is tightly coupled to activation of poised (histone H3 lysine 4 mono- and dimethylated) enhancers, as evidenced by the acquisition of histone H3 lysine 27 acetylation and the binding of MED1, SMC1, and P300 proteins to these regions, as well as to activation of target genes. Intriguingly, formation of loops connecting activated enhancers and promoters is also associated with extensive recruitment of corepressors such as NCoR and HDACs, indicating that this class of coregulators may play a previously unrecognized role during enhancer activation.
Més informació
Petersen R, Lambourne JJ, Javierre BM, Grassi L, Kreuzhuber R, Ruklisa D, Rosa IM, Tomé AR, Elding H, van Geffen JP, Jiang T, Farrow S, Cairns J, Al-Subaie AM, Ashford S, Attwood A, Batista J, Bouman H, Burden F, Choudry FA, Clarke L, Flicek P, Garner SF, Haimel M, Kempster C, Ladopoulos V, Lenaerts AS, Materek PM, McKinney H, Meacham S, Mead D, Nagy M, Penkett CJ, Rendon A, Seyres D, Sun B, Tuna S, van der Weide ME, Wingett SW, Martens JH, Stegle O, Richardson S, Vallier L, Roberts DJ, Freson K, Wernisch L, Stunnenberg HG, Danesh J, Fraser P, Soranzo N, Butterworth AS, Heemskerk JW, Turro E, Spivakov M, Ouwehand WH, Astle WJ, Downes K, Kostadima M, Frontini M

Platelet function is modified by common sequence variation in megakaryocyte super enhancers.

Nat Commun 13 Jul 2017, 8 16058. Epub 13 Jul 2017
Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data and promoter long-range interactions. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions.
Més informació
Burren OS, Rubio García A, Javierre BM, Rainbow DB, Cairns J, Cooper NJ, Lambourne JJ, Schofield E, Castro Dopico X, Ferreira RC, Coulson R, Burden F, Rowlston SP, Downes K, Wingett SW, Frontini M, Ouwehand WH, Fraser P, Spivakov M, Todd JA, Wicker LS, Cutler AJ, Wallace C

Chromosome contacts in activated T cells identify autoimmune disease candidate genes.

Genome Biol. 4 Set 2017, 18 (1) 165. Epub 4 Set 2017
Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4
Més informació
Javierre BM, Burren OS, Wilder SP, Kreuzhuber R, Hill SM, Sewitz S, Cairns J, Wingett SW, Várnai C, Thiecke MJ, Burden F, Farrow S, Cutler AJ, Rehnström K, Downes K, Grassi L, Kostadima M, Freire-Pritchett P, Wang F, Stunnenberg HG, Todd JA, Zerbino DR, Stegle O, Ouwehand WH, Frontini M, Wallace C, Spivakov M, Fraser P

Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters.

Cell 17 Nov 2016, 167 (5) 1369-1384.e19.
Long-range interactions between regulatory elements and gene promoters play key roles in transcriptional regulation. The vast majority of interactions are uncharted, constituting a major missing link in understanding genome control. Here, we use promoter capture Hi-C to identify interacting regions of 31,253 promoters in 17 human primary hematopoietic cell types. We show that promoter interactions are highly cell type specific and enriched for links between active promoters and epigenetically marked enhancers. Promoter interactomes reflect lineage relationships of the hematopoietic tree, consistent with dynamic remodeling of nuclear architecture during differentiation. Interacting regions are enriched in genetic variants linked with altered expression of genes they contact, highlighting their functional role. We exploit this rich resource to connect non-coding disease variants to putative target promoters, prioritizing thousands of disease-candidate genes and implicating disease pathways. Our results demonstrate the power of primary cell promoter interactomes to reveal insights into genomic regulatory mechanisms underlying common diseases.
Més informació
Schoenfelder S, Sugar R, Dimond A, Javierre BM, Armstrong H, Mifsud B, Dimitrova E, Matheson L, Tavares-Cadete F, Furlan-Magaril M, Segonds-Pichon A, Jurkowski W, Wingett SW, Tabbada K, Andrews S, Herman B, LeProust E, Osborne CS, Koseki H, Fraser P, Luscombe NM, Elderkin S

Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome.

Nat. Genet. Oct 2015, 47 (10) 1179-1186. Epub 31 Ago 2015
The Polycomb repressive complexes PRC1 and PRC2 maintain embryonic stem cell (ESC) pluripotency by silencing lineage-specifying developmental regulator genes. Emerging evidence suggests that Polycomb complexes act through controlling spatial genome organization. We show that PRC1 functions as a master regulator of mouse ESC genome architecture by organizing genes in three-dimensional interaction networks. The strongest spatial network is composed of the four Hox gene clusters and early developmental transcription factor genes, the majority of which contact poised enhancers. Removal of Polycomb repression leads to disruption of promoter-promoter contacts in the Hox gene network. In contrast, promoter-enhancer contacts are maintained in the absence of Polycomb repression, with accompanying widespread acquisition of active chromatin signatures at network enhancers and pronounced transcriptional upregulation of network genes. Thus, PRC1 physically constrains developmental transcription factor genes and their enhancers in a silenced but poised spatial network. We propose that the selective release of genes from this spatial network underlies cell fate specification during early embryonic development.
Més informació
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Current projects

Fundación Científica de la Asociación Española Contra el Cáncer, LAB AECC 2021

Responsable:Biola M Javierre
Codi:LABAE21981JAVI
Financiadors:
Data d'inici:01/12/2021
Data de finalització:30/11/2024

Ministerio de Ciencia, Innovación y Universidades , Ayudas para contratos predoctorales para la formacion de doctores (FPI)

Responsable:Biola M Javierre
Codi:PRE2019-088005
Financiadors:
Data d'inici:01/08/2020
Data de finalització:31/07/2024

Wellcome Leap, Human Organs, Physiology, and Engineering (HOPE) Grant, in collaboration with Roser Vento-Tormo (UK), Kyung-Ho Roh (USA) (Australia) and Leonardo Morsut (USA)

Responsable:Biola M Javierre
Codi:HOPE-2021-2754490174
Financiadors:
Data d'inici:01/04/2021
Data de finalització:03/03/2024

2019 European Hematology Association, EHA Advanced Research Grant. Dissecting the role of non-coding genome in B-precursor Acute Lymphoblastic Leukaemia under the THREE-DIMENTIONAL genome architecture point of view [ALL-3D]

Responsable:Biola M Javierre
Codi:4823998
Financiadors:
Data d'inici:01/09/2021
Data de finalització:31/08/2023

Deciphering the Oncogenic Role of the PRC1 Complexes Through Integration of Functional and Spatial Genomics in Diffuse Large B-cell Lymphoma.

Responsable:Biola M Javierre
Codi:08R/2019
Financiadors:
Data d'inici:01/06/2020
Data de finalització:28/02/2023

“La Caixa” Foundation Postdoctoral Junior Leadership-Retaining. Dynamic 3D Chromatin Organization in Human Hematopoiesis: revealing the contributions of non-coding genetic variants and mutations in blood malignancies with the aim of identifying novel disease-associated genes

Responsable:Biola M Javierre
Codi:LCF/BQ/PI19/11690001
Financiadors:
Data d'inici:30/09/2019
Data de finalització:29/09/2022

Dynamic 3D organization of chromatin in human haematopoiesis: description of new genes associated with haematological diseases

Responsable:Biola M Javierre
Codi:RTI2018-094788-A-I00
Financiadors:
Data d'inici:01/01/2019
Data de finalització:31/12/2021

Previous projects

Ayudas para contratos Ramón y Cajal (RYC)

Responsable:Biola M Javierre
Codi:RYC-2016-19655
Financiadors:
Data d'inici:01/03/2018
Data de finalització:30/09/2019

Pharmacological stabilization of therapeutically-useful stem cells.

Responsable:Biola M Javierre
Codi:CMBR 2020
Financiadors:
Data d'inici:01/02/2020
Data de finalització:01/02/2021

2018 L'Oréal España, L'ORÉAL-UNESCO for Woman in Science International Rising Talents

Responsable:Biola M Javierre
Financiadors:
Data d'inici:14/03/2019
Data de finalització:13/03/2020