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

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.

Deciphering the Complexity of 3D Chromatin Organization Driving Lymphopoiesis and Lymphoid Malignancies

“…Memory B cells: The dynamic changes in chromatin state and conformation landscape that occurs upon B cell activation and GC transition are largely reversible as cells progress to the memory stage. The epigenetic landscape, transcriptome, chromatin accessibility and 3D organization of quiescent human naive and memory B cell populations are indeed indistinguishable upon unsupervised clustering, nonetheless clearly separated from GC and plasma mature B cells populations (29). Most of I compartments defined in GC B cells, switch back upon memory B cell transition to a compartment organization similar to naive B cells, erasing this layer of 3D organization imprint and allowing memory B-cells priming for GC re-entry.…”

“…A recent study demonstrated that in B cells, the naive to GC transition is also characterized by compartmentalization changes and the emergence of a new type of weak, Intermediate (I) compartments, which allow for inter-compartment interactions. I compartments in GC B cells arise from A or B compartments and are enriched for the H3K27me3 mark, containing genes repressed by the PRC (29).…”

“…The silencing of Pax5 expression at this stage was proposed to be responsible for overwriting the typical B cell transcriptional program and 3D chromatin organization (60), although only minimal compartment changes were identified. Indeed, plasma cells have been shown to retain a high fraction of I compartments (29), irreversibly locking the 3D chromatin organization.…”

“…A/B-compartment switching has been identified in T and B cell malignancies, albeit the functional and biological consequences of these alterations remain to be determined, in a cell-specific and context-dependent manner. A recent study comparing Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL) patient samples to normal B cells reported that about 25% of the genome undergoes compartmental changes (29). These switches were mostly associated to a global inactivation (A to B) in CLL and activation (B to A) in MCL, suggesting that while similar cellular transformation mechanisms might be in place for these neoplasms supposedly originating from memory and naive B cells, disease-specific 3D chromatin topology alterations might be uncovered (29).…”

“…the A/B compartments, recently the intermediate (I) compartments were also introduced as highly dynamic chromatin domains enriched in genes poised or repressed by the Polycomb Repressive Complex (PRC) (29). At a submegabase level of chromatin organization, we observe selfinteracting domains named topologically associating domains (TADs) (30,31), which appear to be highly conserved across cell type and mammalian species.…”