Enhancer Biology in Development and Cancer
A fundamental question in biology is how gene expression programs are established and maintained to preserve or alter cell identity. This question is intimately related to how transcription factors interact with the appropriate gene-specific cis-regulatory elements within chromatin.
Enhancers are cis-acting DNA sequences that determine cell identity by regulating when, where and how genes are expressed. Despite their importance, the regulatory components controlling the structure and function of enhancers during lineage development and disease pathogenesis remain largely unknown.
We recently developed the CRISPR/Cas9-based ‘CAPTURE’ system to unbiasedly identify chromatin interactions that regulate non-coding genomic elements including enhancers. Using biotinylated dCas9 and programmable sgRNAs, we were able to selectively isolate the native genomic locus-associated protein complexes and 3D chromatin structures (Liu et al., 2017). The CAPTURE system provides a ‘first-in-kind’ approach to simultaneously identify cis-element-regulating proteins and DNA structures, and compare the results to establish the causality of gene expression during development and disorders.
We also developed dCas9-based enhancer-targeting epigenetic perturbation systems, enCRISPRi and enCRISPRa, for high throughput analyses of enhancer function in lineage differentiation and cancer pathogenesis (Li et al., 2020). Building on these discoveries, it is our long-term goal to demystify the cis-regulatory logics as fundamental principles that control stem cell development and disorders.
Ongoing studies in our lab include:
- Elucidating the molecular determinants of lineage-specifying enhancers
- Functional and mechanistic analysis of pathogenic non-coding variants
- Developing genomic and epigenomic editing technologies in dissecting genome structure and function