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

Author/s: Roser Vilarrasa-Blasi, Paula Soler-Vila, Núria Verdaguer-Dot, Núria Russiñol, Marco Di Stefano, Vicente Chapaprieta, Guillem Clot, Irene Farabella, Pol Cuscó, Xabier Agirre, Felipe Prosper, Renée Beekman, Silvia Beà, Dolors Colomer, Hendrik G. Stunnenberg, Ivo Gut, Elias Campo, Marc A. Marti-Renom, José I. Martin-Subero

Abstract

The chromosome conformation dynamics during human cell differentiation and its potential reorganization upon neoplastic transformation is poorly characterized. Here, we integrate in situ Hi-C and nine additional omic layers to define and biologically characterize the three-dimensional (3D) genome topology across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) patients. Beyond conventional active (A) and inactive (B) compartments, an integrative analysis of Hi-C data reveals the presence of a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, we detect that 28% of the compartments change at defined maturation stages and mostly involve the intermediate compartment. The transition from naive to germinal center B cells is associated with widespread chromatin activation, which mostly reverts into the naive state upon further maturation of germinal center cells into memory B cells. The analysis of CLL and MCL neoplastic cells points both to entity and subtype-specific alterations in chromosome organization. Remarkably, we observe that large chromatin blocks containing key disease-specific genes alter their 3D genome organization. These include the inactivation of a 2Mb region containing the EBF1 gene in CLL and the activation of a 6.1Mb region containing the SOX11 gene in clinically aggressive MCL. 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 landscape.

Tracks

Links to visualize all the multi-omics data generated in the present study in the UCSC browser. Although each link directly brings you to a specific region of interest, the entire genome can be browsed:

AICDA region

EBF1 region

KSR2 region

MCL block

3D models

Links to the 3D models of the EBF1 locus to be visualized with TADkit:

CLL

NBC

Hi-C matrices at 20kb

Links to the Hi-C matrices at 20kb visualized by the 3D genome browser (Wang et al., Genome Biology 2018)

NBC

GCBC

PC

MBC

uCLL1

uCLL2

mCLL1

mCLL2

mCLL3

mCLL4

mCLL5

cMCL1

cMCL2

nnMCL1

nnMCL2

nnMCL3