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Identification of non-coding silencer elements and their regulation of gene expression

Nature Reviews Molecular Cell Biology volume 24, pages 383–395 (2023)Cite this article

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Abstract

Cell type- and differentiation-specific gene expression is precisely controlled by genomic non-coding regulatory elements (NCREs), which include promoters, enhancers, silencers and insulators. It is estimated that more than 90% of disease-associated sequence variants lie within the non-coding part of the genome, potentially affecting the activity of NCREs. Consequently, the functional annotation of NCREs is a major driver of genome research. Compared with our knowledge of other regulatory elements, our knowledge of silencers, which are NCREs that repress the transcription of genes, is largely lacking. Multiple recent studies have reported large-scale identification of transcription silencer elements, indicating their importance in homeostasis and disease. In this Review, we discuss the biology of silencers, including methods for their discovery, epigenomic and other characteristics, and modes of function of silencers. We also discuss important silencer-relevant considerations in assessing data from genome-wide association studies and shed light on potential future silencer-based therapeutic applications.

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Fig. 1: Silencer elements and their proposed mechanisms in gene regulation.
Fig. 2: Large-scale silencer identification methods.
Fig. 3: Silencer elements with dual functionality.
Fig. 4: Effects of disrupted silencer function on gene expression and disease.

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Acknowledgements

This work was supported by a KWF Young Investigator Grant from the Dutch Cancer Society (11707) and an ERC Starting Grant from the European Research Council (950655-Silencer) awarded to B.P.

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Author notes

  1. These authors contributed equally: Baoxu Pang, Jan H. van Weerd, Feija L. Hamoen.

Authors and Affiliations

  1. Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands

    Baoxu Pang, Jan H. van Weerd & Feija L. Hamoen

  2. Department of Genetics, Stanford University, Stanford, CA, USA

    Michael P. Snyder

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Contributions

B.P., J.H.v.W. and F.L.H. researched data for the article, wrote the article and reviewed and/or edited the manuscript before submission. M.P.S. contributed substantially to discussion of the content.

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Correspondence to Baoxu Pang or Michael P. Snyder.

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Competing interests

M.P.S. is a founder and member of the science advisory boards of Personalis, SensOmics, Qbio, January, Mirvie and Filtricine, and a member of the science advisory boards of Genapsys and Epinomics. B.P. and M.P.S. hold a patent on the ReSE screening system and method (WO-2021155369-A1).

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Related links

ENCODE: https://www.encodeproject.org/

EnhancerAtlas: http://www.enhanceratlas.org/

SilencerDB: http://health.tsinghua.edu.cn/silencerdb/

VISTA Enhancer Browser: https://enhancer.lbl.gov/

Glossary

Assay for transposase-accessible chromatin using sequencing

(ATAC-seq). A high-throughput technique to identify regions of accessible chromatin genome-wide.

Cardiac QT interval

An electrocardiographic measure of myocardial repolarization.

Chromatin interaction analysis with paired-end tag sequencing

(ChIA-PET). A high-throughput technique to identify genome-wide chromatin interactions mediated by specific factors.

Chromatin looping factors CTCF and cohesion

Architectural proteins that mediate longe-range genomic interactions by contributing to three-dimensional genome organization.

Expression quantitative trait locus

A genomic locus or single-nucleotide polymorphism that is associated with differential gene expression, thereby linking variations in gene expression levels to different genotypes.

Formaldehyde-assisted isolation of regulatory elements

(FAIRE). A high-throughput technique to discover nucleosome-depleted genomic regions, which are indicative of regulatory activity.

Genome-wide association studies

(GWAS). Studies used to identify genomic variants that are statistically associated with a particular trait or disease risk.

Genomic position effects

The influence of the endogenous chromosomal environment on the activity of a gene or a regulatory element.

Hi-C

A chromosome conformation capture technique that maps the three-dimensional organization of the genome.

Insulators

Non-coding regulatory elements with enhancer blocking or barrier function.

Massively parallel reporter assay

(MPRA). A high-throughput technique to simultaneously measure the transcriptional activity of thousands of candidate non-coding regulatory elements.

Self-transcribing active regulatory region sequencing

(STARR-seq). A type of massively parallel reporter assay in which candidate non-coding regulatory elements are cloned downstream of a reporter gene so that their enhancer or silencer activity is reflected in the abundance of the non-coding regulatory element sequence within the pool of plasmid-derived RNA.

‘Shadow’ enhancers

Two or more enhancers with seemingly redundant functions that regulate the same target gene or genes.

Topologically associating domain

Chromatin domain of typically ~100 kb to ~1 Mb, characterized by high intradomain contacts that contribute to NCRE-promoter interactions.

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Pang, B., van Weerd, J.H., Hamoen, F.L. et al. Identification of non-coding silencer elements and their regulation of gene expression. Nat Rev Mol Cell Biol 24, 383–395 (2023). https://doi.org/10.1038/s41580-022-00549-9

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