MAPPING THE THREE-DIMENSIONAL GENOME DYNAMICS IN NORMAL AND NEOPLASTIC B CELLS
EHA Library. Martin-Subero I. 06/17/18; 219220 Topic: 3B T-cell lymphomas and NK-cell neoplasms
Dr. Iñaki Martin-Subero
Dr. Iñaki Martin-Subero
Contributions
Abstract
 


Abstract: LB2602

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 11:30 - 11:45

Location: Room A1

Background

In the recent years, several studies have analyzed the whole-genome landscape of different epigenomic layers in normal B cells and various subtypes of B cell neoplasms. In addition to DNA methylation and chromatin-based epigenetic marks, the three-dimensional (3D) genome structure is becoming an essential piece of information to understand gene (de)regulation. However, this molecular layer has not been explored yet in normal human B cell differentiation or in B cell neoplasms such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).

Aims

Our global aim is to characterize the role and dynamics of the 3D chromatin structure during normal B cell differentiation and upon neoplastic transformation.

Methods

In situ Hi-C sequencing was performed on three biological replicates of four normal human B cell subpopulations including naive B cells (NBC) and memory B cells (MBC) obtained from peripheral blood, and germinal center B cells (GCBC) and plasma cells (PC) from tonsils, as well as on seven CLL and five MCL primary cases (total number of samples = 24). Furthermore, we included whole-genome maps of six different histone marks with non-overlapping functions, chromatin accessibility, DNA methylation and gene expression, which were generated, as part of the BLUEPRINT Consortium, in normal B cells subpopulations and in the same primary CLL and MCL cases in which in situ Hi-C was performed. All the resulting datasets were analyzed by state-of-the-art computational approaches.

Results

Integrating 3D chromatin interactions from in situ Hi-C and histone modifications, we initially categorized the genome into A (active chromatin), B (inactive chromatin) and intermediate compartments in all samples. An unsupervised analysis of the data revealed that normal B cell subpopulations, CLLs and MCLs showed different 3D chromatin configurations. Interestingly, CLLs and MCLs were more similar to NBCs and MBCs, which have been suggested as their cells of origin. Additionally, GCBCs and PCs clustered together and separately from the rest of the samples. A deeper analysis of B cells revealed that 28% of the entire genome modulates its 3D chromatin compaction level during the normal maturation process, a phenomenon that involves genes and pathways related to B cell functions. We next aimed at detecting tumor-specific changes in the level of 3D chromatin interactions. We took the 72% of the regions with conserved 3D structure during normal B cell differentiation and compared them with neoplastic B cells. Remarkably, we observed hundreds of 3D genome alterations (i.e compartment shifts) that were shared by CLL and MCL, as well as alterations that were specific for each neoplasia. Furthermore, we correlated these transitions in the 3D chromatin structure, both in normal and neoplastic B cells, with other epigenetic layers and transcriptional profiles, to shed light onto their complex interplay. For instance, we identified that enhancers and promoter becoming de novo active in neoplastic B cells correlated with increased 3D interactions.

Conclusion

We have characterized, for the first time, the modulation of the genome-wide 3D chromatin structure during the normal human B cell differentiation process and in two B cell neoplasms, CLL and MCL. Although the data are currently being analyzed further, our initial results indicate that the 3D genome is remodeled upon B cell differentiation, and that B cell neoplasms acquire tumor-specific 3D changes that correlate with their altered genome activity.

Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research

Keyword(s): B cell, Chromatin structure, Chronic Lymphocytic Leukemia, Mantle cell lymphoma
 


Abstract: LB2602

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 11:30 - 11:45

Location: Room A1

Background

In the recent years, several studies have analyzed the whole-genome landscape of different epigenomic layers in normal B cells and various subtypes of B cell neoplasms. In addition to DNA methylation and chromatin-based epigenetic marks, the three-dimensional (3D) genome structure is becoming an essential piece of information to understand gene (de)regulation. However, this molecular layer has not been explored yet in normal human B cell differentiation or in B cell neoplasms such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).

Aims

Our global aim is to characterize the role and dynamics of the 3D chromatin structure during normal B cell differentiation and upon neoplastic transformation.

Methods

In situ Hi-C sequencing was performed on three biological replicates of four normal human B cell subpopulations including naive B cells (NBC) and memory B cells (MBC) obtained from peripheral blood, and germinal center B cells (GCBC) and plasma cells (PC) from tonsils, as well as on seven CLL and five MCL primary cases (total number of samples = 24). Furthermore, we included whole-genome maps of six different histone marks with non-overlapping functions, chromatin accessibility, DNA methylation and gene expression, which were generated, as part of the BLUEPRINT Consortium, in normal B cells subpopulations and in the same primary CLL and MCL cases in which in situ Hi-C was performed. All the resulting datasets were analyzed by state-of-the-art computational approaches.

Results

Integrating 3D chromatin interactions from in situ Hi-C and histone modifications, we initially categorized the genome into A (active chromatin), B (inactive chromatin) and intermediate compartments in all samples. An unsupervised analysis of the data revealed that normal B cell subpopulations, CLLs and MCLs showed different 3D chromatin configurations. Interestingly, CLLs and MCLs were more similar to NBCs and MBCs, which have been suggested as their cells of origin. Additionally, GCBCs and PCs clustered together and separately from the rest of the samples. A deeper analysis of B cells revealed that 28% of the entire genome modulates its 3D chromatin compaction level during the normal maturation process, a phenomenon that involves genes and pathways related to B cell functions. We next aimed at detecting tumor-specific changes in the level of 3D chromatin interactions. We took the 72% of the regions with conserved 3D structure during normal B cell differentiation and compared them with neoplastic B cells. Remarkably, we observed hundreds of 3D genome alterations (i.e compartment shifts) that were shared by CLL and MCL, as well as alterations that were specific for each neoplasia. Furthermore, we correlated these transitions in the 3D chromatin structure, both in normal and neoplastic B cells, with other epigenetic layers and transcriptional profiles, to shed light onto their complex interplay. For instance, we identified that enhancers and promoter becoming de novo active in neoplastic B cells correlated with increased 3D interactions.

Conclusion

We have characterized, for the first time, the modulation of the genome-wide 3D chromatin structure during the normal human B cell differentiation process and in two B cell neoplasms, CLL and MCL. Although the data are currently being analyzed further, our initial results indicate that the 3D genome is remodeled upon B cell differentiation, and that B cell neoplasms acquire tumor-specific 3D changes that correlate with their altered genome activity.

Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research

Keyword(s): B cell, Chromatin structure, Chronic Lymphocytic Leukemia, Mantle cell lymphoma

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