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

Roser Vilarrasa‐Blasi ,Pol Cuscó,Núria Russiñol,Núria Verdaguer-Dot,Renée Beekman,Elı́as Campo ,Marc A Martı́-Renom ,Marco Di Stefano,Felipe Prósper ,Marta Kulis,Sı́lvia Beà ,Marta Gut ,Guillem Clot,Irene Farabella,Paula Soler-Vila,Vicente Chapaprieta,Xabier Agirre,Dolors Colomer,Hendrik G Stunnenberg,José I Martín‐Subero

doi:10.1038/s41467-020-20849-y

Abstract

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.

Highlights

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 high-throughput chromosome conformation capture (Hi-C) and nine additional omics layers
The comparison of samples suggests that the overall genome architecture of naive B cells (NBC) is more similar to memory B cells (MBC) and clearly different from germinal center B cells (GCBC) and plasma cells (PC), which belong to a different cluster (Fig. 1c)
In contrast to other omics marks, the first component of DNA methylation data resulted in a division of GCBC, MBC, and PC separated from the NBC

Summary

Introduction

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. Alternative subdivisions of genome compartmentalization have been proposed, including three compartments[11] or even six compartment subtypes with distinct genomic and epigenomic features[12] All of these studies highlight the role of three-dimensional (3D) genome organization in the regulatory decisions associated with cell fate. Previous reports have identified that B cell maturation and neoplastic transformation to CLL or MCL entail extensive modulation of the DNA methylome and histone modifications[29,30,31,32,33,34] Whether such epigenetic changes are linked to modulation of the higher-order chromosome organization is yet unknown[35]

Methods

Results

Conclusion