Interrogation of enhancer function by enhancer-targeting CRISPR epigenetic editing

Kailong Li, Yuxuan Liu, Hui Cao, Yuannyu Zhang, Zhimin Gu, Xin Liu, Andy Yu, Pranita Kaphle, Kathryn E. Dickerson, Min Ni and Jian Xu ()
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Kailong Li: University of Texas Southwestern Medical Center
Yuxuan Liu: University of Texas Southwestern Medical Center
Hui Cao: University of Texas Southwestern Medical Center
Yuannyu Zhang: University of Texas Southwestern Medical Center
Zhimin Gu: University of Texas Southwestern Medical Center
Xin Liu: University of Texas Southwestern Medical Center
Andy Yu: University of Texas Southwestern Medical Center
Pranita Kaphle: University of Texas Southwestern Medical Center
Kathryn E. Dickerson: University of Texas Southwestern Medical Center
Min Ni: University of Texas Southwestern Medical Center
Jian Xu: University of Texas Southwestern Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Tissue-specific gene expression requires coordinated control of gene-proximal and -distal cis-regulatory elements (CREs), yet functional analysis of gene-distal CREs such as enhancers remains challenging. Here we describe CRISPR/dCas9-based enhancer-targeting epigenetic editing systems, enCRISPRa and enCRISPRi, for efficient analysis of enhancer function in situ and in vivo. Using dual effectors capable of re-writing enhancer-associated chromatin modifications, we show that enCRISPRa and enCRISPRi modulate gene transcription by remodeling local epigenetic landscapes at sgRNA-targeted enhancers and associated genes. Comparing with existing methods, the improved systems display more robust perturbations of enhancer activity and gene transcription with minimal off-targets. Allele-specific targeting of enCRISPRa to oncogenic TAL1 super-enhancer modulates TAL1 expression and cancer progression in xenotransplants. Single or multi-loci perturbations of lineage-specific enhancers using an enCRISPRi knock-in mouse establish in vivo evidence for lineage-restricted essentiality of developmental enhancers during hematopoiesis. Hence, enhancer-targeting CRISPR epigenetic editing provides opportunities for interrogating enhancer function in native biological contexts.

Date: 2020
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DOI: 10.1038/s41467-020-14362-5

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