Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

To investigate the three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia and mantle cell lymphoma patients, here we integrate in situ Hi-C and nine additional omics layers. Beyond conventional active (A) and inactive (B) compartments, we uncover a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, 28% of the compartments change, mostly involving a widespread chromatin activation from naive to germinal center B cells and a reversal to the naive state upon further maturation into memory B cells. B cell neoplasms are characterized by both entity and subtype-specific alterations in 3D genome organization, including large chromatin blocks spanning key disease-specific genes. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.This research was funded by the European Union’s Seventh Framework Programme through the Blueprint Consortium (grant agreement 282510), the World Wide Cancer Research Foundation Grant No. 16-1285 (to J.I.M.-S.), the ERC (grant agreement 609989 to M.A.M.-R.), European Union’s Horizon 2020 research and innovation programme (grant agreement 676556 to M.A.M.-R.). We also knowledge the support of Spanish Ministerio de Ciencia, Innovación y Universidades through SAF2012-31138 and SAF2017-86126-R to J.I.M.-S., SAF2015-64885-R to E.C., BFU2017-85926-P to M.A.M.-R. and PMP15/00007 to E.C. which is part of Plan Nacional de I + D + I and co-financed by the ISCIII-Sub-Directorate General for Evaluation and the European Regional Development Fund (FEDER-“Una manera de Hacer Europa”) (to E.C.), the International Cancer Genome Consortium (Chronic Lymphocytic Leukemia Genome consortium to E.C.), La Caixa Foundation (CLLEvolution-HE17-00221, to E.C.). Furthermore, the authors would like to thank the support of the Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-736 (to J.I.M.-S.), 2017-SGR-1142 (to E.C.) and 2017-SGR-468 (to E.C.), the Accelerator award CRUK/AIRC/AECC joint funder-partnership, the CERCA Programme/Generalitat de Catalunya and CIBERONC (CB16/12/00225, CB16/12/00334, and CB16/12/00489). R.V.-B. (BES-2013-064328) and P.S.-V. (BES-2014-070327) were supported by a predoctoral FPI Fellowship from the Spanish Government. CRG acknowledges support from ‘Centro de Excelencia Severo Ochoa 2013-2017’, SEV-2012-0208 and the CERCA Programme/Generalitat de Catalunya as well as support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III and the EMBL partnership, the Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement, and the Cofinancing with funds from the European Regional Development Fund (ERDF) by the Spanish Ministry of Science and Innovation coresponding to the Programa Opertaivo FEDER Plurirregional de España (POPE) 2014-2020 and by the Secretaria d’Universitats i Recerca, Departament d’Empresa i Coneixement of the Generalitat de Catalunya corresponding to the programa Operatiu FEDER Catalunya 2014-202