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Liu Lab / Research
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Research
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Form: the 3D genome

We are developing super-resolution and electron microscopy based methods to directly visualize nano-scale organization and ultrastructure of the 3D genome. By lattice light-sheet microscopy and residence-time thresholding at the single-molecule level, we can systematically map stable TF binding sites in single live cells (Liu et al, 2014; Xie & Peng, 2022). Another method – 3D ATAC-PALM combines ATAC (Assay for Transposase-Accessible Chromatin) with lattice light-sheet PALM microscopy to selectively image nano-scale organization of the accessible genome (Xie & Peng, 2020). Coupled with chemical and genetic perturbations, these methods enabled investigation of molecular identities and interactions contributing to the formation and maintenance of 3D genome organization. We found that Yap protein hubs promote de novo formation of accessible chromatin domains (Cai et al, 2019). By analyzing auxin induced degron cell lines, we found that genome architectural protein CTCF decompacts accessible chromatin (Xie & Peng, 2020). On the contrary, Cohesin prevents spatial mixing of accessible chromatin by counterbalancing affinity interactions mediated by Brd2 (Xie & Peng, 2022).

           

 

Function: how the 3D genome regulates gene expression

          By single cell sequencing and spatial genome imaging, we recently discovered that, instead of dictating population-wide gene expression levels, 3D genome topology mediated by Cohesin safeguards long-distance gene co-expression correlations in single cells (Peng et al, bioRxiv). Currently, we are developing spatial multiomic imaging strategies to study mechanisms underlying this layer of regulation.

 

Links between form and function: Molecules

We devise imaging strategies to characterize molecular dynamics in living cells at the single-molecule level (Chen et al, 2014; Li et al, 2016; Liu et al, 2018). We apply these techniques to examine the interplay between 3D genome organization and transcription factor dynamics (Liu et al, 2014; Xie & Peng, 2022; Peng et al, bioRxiv). In addition, we analyzed live-cell dynamics of CRSPR/Cas9 (Knight et al, 2015), transcription factors during B-cell activation (Kieffer-Kwon et al, 2017), cancer inducing TF hubs (Chong et al, 2018), MeCP2 and its Rett syndrome mutations (Piccolo et al, 2019), 'chemigenetic' sensor (Abdelfattah et al, 2019) and ecDNAs (Hung et al, 2021; Lange et al, 2022) with our collaborators.