CRISPR-based epigenome editing integrates the precision of CRISPR with the capability of epigenetic mark rewriting, offering a tunable and reversible gene regulation strategy without altering the DNA sequences. Various epigenome editing systems have been developed and applied in different organisms and cell types; however, the detailed information is discrete, making it challenging to evaluate the precision of different editing systems and design the optimal sgRNAs for further functional studies. Herein, we developed CRISPRepi (http://crisprepi.maolab.org/ or http://crisprepi.lilab-pkuhsc.org/), a pioneering platform that consolidates extensive sequencing data from 671 meticulously curated RNA-seq, ChIP-seq, Bisulfite-seq and ATAC-seq datasets in 87 cell types manipulated by 74 epigenome editing systems. In total, we have curated 5962 sgRNAs associated with 283 target genes from 2277 samples across six species. CRISPRepi incorporates tools for analyzing editing outcomes and assessing off-target effects by analyzing gene expression changes pre- and post-editing, along with the details of multi-omic epigenetic landscapes. Moreover, CRISPRepi supports the investigation of editing potentials for newly designed sgRNA sequences in a cell/tissue-specific context. By providing a user-friendly interface for searching and selecting optimal editing designs across multiple organisms, CRISPRepi serves as an integrated resource for researchers to evaluate editing efficiency and off-target effects among diverse CRISPR-based epigenome editing systems.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with high morbidity and mortality worldwide. Although the dysregulation of BARX1 expression has been shown to be associated with malignant cancers, including NSCLC, the underlying mechanism remains elusive. In this study, we identified BARX1 as a common differentially expressed gene in lung squamous cell carcinoma and adenocarcinoma. Importantly, we uncovered a novel mechanism behind the regulation of BARX1, in which ZFP36 interacted with 3’UTR of BARX1 mRNA to mediate its destabilization. Loss of ZFP36 led to the upregulation of BARX1, which further promoted the proliferation, migration and invasion of NSCLC cells. In addition, the knockdown of BARX1 inhibited tumorigenicity in mouse xenograft. We demonstrated that BARX1 promoted the malignant phenotypes by transactivating a set of master oncogenes involved in the cell cycle, DNA synthesis and metastasis. Overall, our study provides insights into the mechanism of BARX1 actions in NSCLC and aids a better understanding of NSCLC pathogenesis.

Summary: Significant efforts have been made to identify and validate oncoproteins and ncRNAs as therapeutic targets for cancer therapy; however, emerging observations suggest that noncoding cis-regulatory elements, which orchestrate the 3D organization of the genome and thus the transcriptional landscape, are potential therapeutic targets as well. In this commentary, we envisage that further efforts to decipher the noncoding cis-regulatory code and performing systematic surveys of functional noncoding cis-regulatory elements and recurrent 3D genome alterations in both cancerous and nonmalignant cells within tumor tissues will pave the way to the development of novel therapeutic strategies.

Pancreatic cancer is a leading cause of cancer death due to its early metastasis and limited response to the current therapies. Metastasis is a complicated multistep process, which is determined by complex genetic alterations. Despite the identification of many metastasis-related genes, distinguishing the drivers from numerous passengers and establishing the causality in cancer pathophysiology remains challenging. Here, we established a high-throughput and piggyBac transposon-based genetic screening platform, which enables either reduced or increased expression of chromosomal genes near the incorporation site of the gene search vector cassette that contains a doxycycline-regulated promoter. Using this strategy, we identified YWHAZ as a key regulator of pancreatic cancer metastasis. We demonstrated that functional activation of Ywhaz by the gene search vector led to enhanced metastatic capability in mouse pancreatic cancer cells. The metastasis-promoting role of YWHAZ was further validated in human pancreatic cancer cells. Overexpression of YWHAZ resulted in more aggressive metastatic phenotypes in vitro and a shorter survival rate in vivo by modulating epithelial-to-mesenchymal transition. Hence, our study established a high-throughput screening method to investigate the functional relevance of novel genes and validated YWHAZ as a key regulator of pancreatic cancer metastasis.