Organització 3D de la Cromatina

  • 3D Chromatin January 2019
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

We are a group of passionate scientists with an insatiable thirst for learning about spatio-temporal organization of the DNA.

Our group combines cutting-edge experimental and bioinformatics approaches to understand the specific 3D chromatin organization of haematopoietic cells and its alteration in blood cancers. Our long-term goal is to keep taking steps forwards in the fight against cancer.  We will be unstoppable until we cure it. To do so, we have established a close collaboration with the Barcelona Supercomputing Center (https://www.bsc.es/) and we have the privilege of using the MareNostrum supercomputer.

We are currently seeking enthusiastic new members; so if you are interested in studying chromatin organization, please contact us.

Research

Every cell in our body has about 2 metres of linear DNA containing the genes that shape our being. This DNA, which is the same in every cell, is not-randomly packed into the nucleus of a few microns diameter, and the manner in which it is wrapped plays a fundamental role in regulating genome function.  In some cases it does this by putting regulatory elements, such as enhancer, and target gene promoters into physical contact.  In fact, this can partially explain how cells encoding the same genetic information are phenotypically and functionally different.It has been estimated that the genome harbours around one million regulatory elements, some of these are cell-type specific, but the vast majority of interactions between these elements and the corresponding regulated gene are uncharted, constituting a major missing link in understanding genome control.

Chromatin interactions are crucial for cellular health due to their main role in genome expression regulation and errors in these interactions give rise to the development of a broad range of diseases including blood cancer. The investigation of these altered 3D structures can help us to improve our knowledge of the tumour process, providing new opportunities for the development of novel treatment approaches and diagnostic strategies.

Additionally, genetic studies have identified thousands of single nucleotide polymorphisms and mutations associated with blood cancer, but most of them expand non-coding regions, which makes them difficult to interpret. Interestingly these non-coding genetic variants cluster on DNA hypersensitivity sites, which are the hallmark of a regulatory element, pointing to a potential role for these genetic variants in the deregulation of target genes. By studying the physical interactions between gene promoter and regulatory elements we are able to connect blood cancer genetic alterations to putative target genes, prioritizing new disease-candidate genes and pathways, and revealing insights into genomic regulatory mechanisms underlying cancer. The interpretation of non-coding variation will also help us to improve the prediction of patient outcome as well as allowing us to design better and more personalized treatments.

The main research goals of our lab are:

  • Defining the cell type-specific 3D chromatin organization in human haematopoietic cells
  • Identifying the altered DNA topology in blood cancer
  • Prioritizing new candidate genes and pathways related to blood cancer

3D Chromatin Organization Research Group's webpage: https://www.javierrelab.com/

Twitter: @JavierreLab

Awards

Spanish National Prize L’ORÉAL-UNESCO For Women in Science 2018/2019.

L'Oréal_UNESCO International Rising Talent Award for Women in Science. 2019/2020.

 

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
Show all publications

Current projects

“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

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

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:01/06/2021

EHA Advance 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
Financiadors:
Data d'inici:01/04/2021
Data de finalització:31/03/2023

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