The Roles of SWI/SNF Chromatin Remodelling Complexes and Centromere Proteins Across the Genome
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Embargo End Date
2026-11-18
ICR Authors
Authors
Wu, L
Document Type
Thesis or Dissertation
Date
2025-11-18
Date Accepted
Abstract
The thesis will first explore the roles of the human SWI/SNF chromatin remodelling complexes at centromeres. We find that loss of function of the SWI/SNF subunit PBRM1 results in the dysregulation of centromere structure and function. Genome-wide mapping of the SWI/SNF subunit SMARCA4 and PBAF-specific subunit PBRM1 in wildtype cells demonstrate that the two subunits are associated with pericentromeres. Mapping of SMARCA4 in PBRM1 knockout cells shows that PBRM1 loss results in changes in SMARCA4 association at centromeres, indicating that PBRM1 is required for PBAF’s recruitment to centromeres. Genome-wide mapping of the histone modification H3K9me2 and H3K9me3 in wildtype and PBRM1 knockout cells show changes in heterochromatin upon PBRM1 loss.
The next part of the thesis will describe the roles of centromere protein CENPB along chromosome arms. We find that CENPB is localised to open chromatin regions outside centromeres in an epithelial cell line, including gene promoters. Ectopic CENPB binding sites do not contain the CENPB-box motif, suggesting an alternative mode of recruitment from the centromeres. Motif-based sequence analysis shows a significant enrichment of the CCAAT box motif within these promoters which could represent a potential mode of CENPB recruitment. CENPB also exhibits binding at gene promoters in a leukaemia cell line. There are some overlaps in binding sites between the epithelial and the cancer-derived cells, suggesting cell type specificity in CENPB’s activity at gene promoters. We found that CENPB can potentially act as a transcriptional regulator of these target genes through transcriptomic analysis of CENPB-depleted cells. These findings demonstrate a non-canonical role of CENPB as a possible transcriptional regulator and raises questions about the molecular mechanisms of CENPB recruitment to promoters and regulation of gene transcription.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Genome Stability