Nature communicationsFeb 11, 2026

dHyperCas12a allows simultaneous CRISPR interference of multiple genes

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

dHyperLbCas12a enables highly multiplexed activation and repression to test how regulatory elements combine to shape gene expression.

Evidence

This CRISPR platform study combined hyper-efficient with RNA Polymerase II long arrays and demonstrated activation, repression, simultaneous control, and combinatorial CRE perturbation in primary immune cells and induced pluripotent stem cell differentiation.

Caveat

The abstract reports tool performance and gene-expression perturbation in cellular systems, not organism-level or clinical outcomes.

Simplified

Interactions between genes or cis-regulatory elements (CREs) underlie many biological processes. High-throughput CRISPR screens have allowed researchers to assess the impact of activation or repression of gene and regulatory elements on many phenotypes. However, assessment of interactions between those genes or elements remains limited. To enable efficient highly-multiplexed control of regulatory element activity, we combine a hyper-efficient version of Lachnospiraceae bacterium (dHyperLbCas12a) with RNA Polymerase II expression of long CRISPR RNA () arrays. We demonstrate this system with several activation and repression domains, in cultured primary immune cells, and to differentiate induced pluripotent stem cells. We also develop approaches to use dCas12a for simultaneous activation and repression. Lastly, we demonstrate that dHyperLbCas12a effectors can be used to dissect the independent and combinatorial contributions of CREs to gene expression. These tools create possibilities for highly multiplexed control of gene expression in many biological systems.

Key numbers

85%

Repression Rate

Repression of hexokinase domain containing 1 gene in HepG2 cells.

7×

Target Sites Increase

dEnAsCas12a recognizes several non-canonical sequences.

2500-fold

Multiplexed Activation Range

Effectiveness of dHyperLbCas12a-P300 in A549 cells.

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dHyperCas12a allows simultaneous CRISPR interference of multiple genes

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