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Gene regulation

Understanding the logic and grammar of cis-regulatory elements

Nature Reviews Genetics volume 26, page 665 (2025)Cite this article

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Cis-regulatory elements (CREs), such as promoters and enhancers, possess complex architectures of transcription factors that determine specific expression patterns, levels and responses to diverse cellular or environmental cues. Understanding the rules that drive such specificity has been the holy grail of molecular biology for more than four decades. This knowledge could be used to determine disease mechanisms and design synthetic CREs for therapeutic or bioengineering purposes.

Thousands of studies from the 1980s, 1990s and 2000s used reporter assays to test the activities of individual CREs and how they are affected by selected mutations of putative transcription factor binding sites. This body of work showed that predicting CRE activity was more challenging than anticipated, suggesting that a thorough mechanistic understanding would require evaluating thousands of CRE sequences. In 2012, two seminal studies by Melnikov et al. and Patwardhan et al. tackled this grand challenge by leveraging two key advances at the time: the synthesis of large, complex oligonucleotide pools and measurement of the activity of thousands of CRE variants in parallel using high-throughput sequencing. While presenting these papers at a journal club during my postdoc, I clearly recall the sense that they would transform how CREs are studied.

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  1. Biology Department, Boston University, Boston, MA, USA

    Juan I. Fuxman Bass

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  1. Juan I. Fuxman Bass
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Correspondence to Juan I. Fuxman Bass.

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Fuxman Bass, J.I. Understanding the logic and grammar of cis-regulatory elements. Nat Rev Genet 26, 665 (2025). https://doi.org/10.1038/s41576-025-00847-w

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