ICB Seminar

04.02.2019

3D genome organization and cell fate in development

Dr. Boyan Bonev, Helmholtz Pioneer Campus

Understanding how epigenome variation can lead to the emergence of different cell types during development and evolution is one of the key challenges in modern biology. 3D nuclear architecture represents one major component of such variation and has emerged as an important regulator of gene expression in health and disease. Yet, how chromatin contacts change during development and what are the consequences for cell fate remain unclear.   

Using ultra-high resolution Hi-C we mapped comprehensively 3D chromatin organization during mouse neural development, both in vitro and in vivo. We discovered that gene expression is highly correlated with chromatin insulation, as well as promoter-promoter interactions, but activation of transcription is insufficient to create such topology de novo. Surprisingly, we found that highly transcribed, exon-rich genes frequently engage in long-range contacts both in pluripotent and differentiated cells.

In addition to stable loops, we found dynamic rearrangement of chromatin interactions at various scales during neural differentiation. An extensive Polycomb network in stem cells was disrupted independently of H3K27me3, while novel interactions associated with neuronal transcription factors were established. Finally, most enhancer-promoter interactions appear to be dynamic and established concomitant with gene activation. 

Collectively, this work suggests that 3D nuclear architecture represents an additional layer in the regulation of gene expression and cell fate during development. Yet understanding how the epigenome is related to gene expression at the single cell level remains a challenge. I will also discuss ongoing efforts to determine how cell heterogeneity emerges in the brain using single-cell multi-omics approaches.

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