Transcription regulation during the S phase  
  • ​The S phase is a particularly vulnerable period for cells, as they must accurately replicate both their genetic and epigenetic information
  • Chromatin is more accessible during the S phase to allow origin firing and replication elongation, yet cells somehow prevent promiscuous transcription from initiating
  • We are uncovering critical control mechanisms that prevent dangerous transcription in S phase that would otherwise alter cell identity, induce DNA damage, and cause genomic instability

Spatiotemporal dynamics of phase-separated condensates during S phase​

  • Transcription and replication initiate in spatially-separated foci and this prevents detrimental transcription-replication conflicts (TRCs)
  • Transcription foci are thought to be phase-separated condensates 
  • We study the mechanisms that control focus assembly, movement, and disassembly to account for the dynamic replication program 

DNA replication stress as a driver of epigenetic instability in cancer​​ ​


  • Epigenetic information, including histone marks and 3D chromatin conformation, ensures the pattern of gene expression in different cell types and creates a barrier to cell state transitions
  • Epigenetic instability underlies non-genetic factors contributing to malignant transformation
    • Epigenetic heterogeneity
    • Cell state plasticity
    • Transcription program rewiring
  • The drivers of epigenetic instability are poorly understood.
 
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  • We are investigating the role of DNA replication stress as a driver of epigenetic instability in cancer
    • Replication stress disrupts the normal process of histone recycling
    • Replication stress also alters the histone locus body and histone biosynthesis
  • We model the early steps of transformation by over-expression of key oncogenes that induce replication stress
  • We use novel live-imaging approaches, ChIP-seq, and HiChIP-seq