OBF1 and Oct factors control the germinal center transcriptional program

Song, Shuang. OBF1 and Oct factors control the germinal center transcriptional program. 2021, Doctoral Thesis, University of Basel, Associated Institution, Faculty of Science.


Official URL: https://edoc.unibas.ch/82741/

Downloads: Statistics Overview


Germinal centers (GCs) are an essential structure of the humoral immune response. GC formation begins in the periphery lymphoid organs when follicular B cells encounter blood borne antigens. During the GC reaction, GC B cells undergo a series of molecular events, which ultimately lead to the generation of antibody-secreting plasma cells (PCs) and memory B cells (Bmems). Due to the mutagenic nature of GC B cells, GCs give rise to majority of non-Hodgkin lymphomas (NHLs), including Burkitt’s lymphomas (BL) and most diffuse large B-cell lymphomas (DLBCL). OCT1 and OCT2 are transcription factors (TFs) of the POU family. They recognize the same set of octamer motif and derivatives thereof. OBF1 is a B cell-specific coactivator which interacts with OCT1 and/or OCT2 on binding sites. OCT2 and OBF1 have been shown to be critical for GC formation. However, so far, the functional relevance of OCT1 in B cell or GC formation is largely overlooked. Moreover, little is known about which stage of GC formation is dependent on OCT2 and OBF1. Furthermore, the mechanisms how these factors regulate GC specific target genes and GC process remain elusive.
The main part of this thesis deals with the genomic analysis of OCT1, OCT2 and OBF1 in B cells to understand their functional relevance in GC formation and GC-derived lymphoma cells. Previous work from our laboratory and other groups has demonstrated that OBF1 and OCT2 are indispensable for GC formation. We mapped the global binding pattern of these three factors, and interrogated the mechanisms of these factors in GC transcriptional program using genomic approaches and computational analysis. We found that these factors extensively co-localize with each other and with ETS factors. We confirmed that OBF1 stabilizes the genomic binding of OCT1 on chromatin. Moreover, we revealed that OBF1 maintains the GC transcriptional program by activating the expression of BCL6 and repressing the expression of IRF4. We demonstrated that the proliferation of GC-derived B lymphoma cells is dependent on OBF1, and that loss of OBF1 leads to GC exit and the initiation of post-GC differentiation program. Furthermore, we showed that OBF1 binds to the regulatory elements of GC-related genes in primary murine and human GC B cells. We discovered that depletion of OBF1 in B lymphoma cells was correlated with an upregulation of genes associated with favorable prognosis.
Therefore, OBF1 maintains the integrity of the GC regulatory network, and represents a promising therapeutic target for GC-derived B lymphoma cells.
The second part addresses the enhancer dynamics of stages in B cell differentiation. We performed and compared the ChIP-seq for H3K4me3, H3K4me1, H3K27ac, H3K27me3 and H3K9me2 in haematopoietic stem cells (HSCs), pro-B cells and splenic mature B cells. In contrast to the prevailing model – stage specific enhancer repertoire is primed in the early developmental stages prior to terminal differentiation, we found that the majority of enhancers are de novo established in the stage where their functions are required, without being primed in the preceding stages. Moreover, we confirmed that the H3K9me2 landscape is largely unchanged during the differentiation from HSCs to splenic mature B cells, and that enhancer dynamics are largely uncoupled with PcG-mediated silencing. In sum, our data shed new light on the epigenomic reprogramming during the progression from stem cells to differentiated cells.
Therefore, in this thesis, I demonstrate extensive genomic co-occupancy between OCT factors and OBF1, as well as ETS factors. I identify the target genes of OBF1 and functional mechanisms in regulating the GC reaction. In particular, I uncover the detailed functional dependence of OBF1 in controlling the proliferation of GC-derived B lymphoma cells, and propose it to be a novel therapeutic target for future B lymphoma treatment.
Advisors:Matthias, Patrick and Finke, Daniela
Faculties and Departments:09 Associated Institutions > Friedrich Miescher Institut FMI > Epigenetics > Transcriptional and epigenetic networks and function of histone deacetylases in mammals (Matthias)
UniBasel Contributors:Finke, Daniela
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14113
Thesis status:Complete
Number of Pages:203
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss141132
edoc DOI:
Last Modified:25 Jun 2021 04:30
Deposited On:24 Jun 2021 10:17

Repository Staff Only: item control page