WEHI PhD Completion Seminar hosted by Professor Stephen Nutt

Junli Nie

PhD Student – Nutt Laboratory, Immunology division, WEHI

The landscape of B cell transcriptional regulation
 

Davis Auditorium

Join via TEAMS

Including Q&A session

B cells are key players in the immune system, being the sole source of the antibody that is essential for protective immunity. During B cell development and differentiation, the transcriptome undergoes dramatic changes. To elucidate the regulatory mechanisms underlying these alterations, I used a multi-OMIC approach to integrate transcriptome, chromatin accessibility, and histone modifications across seven representative B cell stages in the mouse. Active profiles, including transcriptome, chromatin accessibility, and H3K27ac, correlated well with B cell biology, whereas the repressive mark H3K27me3 did not. Transcriptional regulation relies on both promoters and enhancers, but with distinct regulation patterns across B cell differentiation. Transcription factors (TFs) play a crucial role in transcriptional regulation by binding to accessible chromatin. Using a novel statistical method, I identified key TFs involved in B cell transcriptional regulation.

Natural genomic variation in the human population is well known to play a major role in the susceptibility to many diseases, including B-cell-associated autoimmune diseases such as lupus. In the second part of my PhD study, I investigated the impact of genomic variation on B cell transcriptional regulation using F1 mice (C57BL/6 x CAST/EiJ) derived from two highly divergent mouse strains that carry more than 22 million genetic variants. I found that the transcriptomes are highly conserved between the two alleles, while the chromatin accessibility shows considerable variation. Variants in TF binding motifs led to differential TF binding and chromatin accessibility, which could be validated by experimental TF binding data or predicted using my novel statistical method. Notably, the conserved transcriptomes were maintained through compensatory mechanisms, where loss-of-function variants in one accessible chromatin region were offset by gain-of-function variants in another regulatory region in the same allele.

In summary, my PhD study provides insights into the complex interplay between chromatin accessibility, histone modifications, and TFs in regulating transcription and establishes a pipeline for investigating the effects of variants on B cell transcriptional regulation.

All welcome!