Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay
Abstract
Learning to read and write the transcriptional regulatory code is of central importance to progress in genetic analysis and engineering. Here we describe a massively parallel reporter assay (MPRA) that facilitates the systematic dissection of transcriptional regulatory elements. In MPRA, microarray-synthesized DNA regulatory elements and unique sequence tags are cloned into plasmids to generate a library of reporter constructs. These constructs are transfected into cells and tag expression is assayed by high-throughput sequencing. We apply MPRA to compare >27,000 variants of two inducible enhancers in human cells: a synthetic cAMP-regulated enhancer and the virus-inducible interferon-β enhancer. We first show that the resulting data define accurate maps of functional transcription factor binding sites in both enhancers at single-nucleotide resolution. We then use the data to train quantitative sequence-activity models (QSAMs) of the two enhancers. We show that QSAMs from two cellular states can be combined to design enhancer variants that optimize potentially conflicting objectives, such as maximizing induced activity while minimizing basal activity.
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A major advantage of MPRAs is that sequences to be tested can simply be synthesized, enabling straightforward saturation mutagenesis and programming synthetic enhancers.
“A major advantage of MPRAs is that sequences to be tested can simply be synthesized, enabling straightforward saturation mutagenesis [G] of enhancers67,184,185 as well as programming synthetic enhancers to inform modelling of their properties186,187.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [184]
Current CRISPR sgRNA libraries can be decoded directly via the CROP-seq vector, while other perturbations, such as ORFs or non-coding elements, can be tagged with short barcodes.
“Existing CRISPR sgRNA libraries can be read out directly (using the CROP-seq vector) while other perturbations (e.g., ORFs, non-coding sequences) can be paired with short barcodes (Melnikov et al., 2012; Yang et al., 2011).”
From Optical Pooled Screens in Human Cells (2019) · cites this paper as Melnikov et al., 2012
Massively parallel reporter assays and CRISPR genome editing have matured rapidly to enable functional characterization of targeted sequence perturbations at scale.
“To address this, there has been rapid maturation of technologies, such as massively parallel reporter assays121–123 and CRISPR genome editing, to support functional characterization of targeted sequence perturbations at scale.”
From A brief history of human disease genetics (2020) · cites this paper as [122]
The PESCA platform extends previous paralleled reporter assays carried out using bulk tissue or sorted cells by including a single-cell RNA-seq-based readout to evaluate the cell-type-specificity of gene expression.
“The PESCA platform extends previous paralleled reporter assays (Hartl et al., 2017; Inoue et al., 2017; Melnikov et al., 2012; Murtha et al., 2014; Patwardhan et al., 2012; Shen et al., 2016) carried out using bulk tissue or sorted cells by including a single-cell RNA-seq-based readout (Cao et al., 2017; Hrvatin et al., 2018; Klein et al., 2015; Macosko et al., 2015; Rosenberg et al., 2018; Stroud”
From A scalable platform for the development of cell-type-specific viral drivers (2019) · cites this paper as Melnikov et al., 2012
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Self-citation
- Authors
- Melnikov, A., Murugan, A., Zhang, X., Tesileanu, T., Wang, L., Rogov, P., Feizi, S., Gnirke, A., Callan, C. G., Kinney, J. B., Kellis, M., Lander, E. S., & Mikkelsen, T. S.
- Affiliations
- Broad Institute (US)
- Princeton University (US)
- Cold Spring Harbor Laboratory (US)
- Corresponding author
- Mikkelsen, Tarjei S
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2012-02-26
- Volume
- 30
- Issue
- 3
- Pages
- 271-277
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC3297981
- OpenAlex
- W2023386301
- Cited by
- 711
- References
- 31
- Citations by year
- 2026: 52 · 2025: 56 · 2024: 47 · 2023: 40 · 2022: 40 · 2021: 55 · 2020: 55 · 2019: 62 · 2018: 53 · 2017: 48 · 2016: 56 · 2015: 49 · 2014: 44 · 2013: 31 · 2012: 22
- FWCI
- 18.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Human Genome Research Institute (R01HG004037)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- enhancers, massively parallel reporter assay, synthetic enhancers, transcription factor binding sites, transcriptional regulation, human cells
- MeSH terms
- Base Sequence, Binding Sites, Biological Assay, Enhancer Elements, Genetic, Humans, Models, Genetic, Molecular Sequence Data, Transcription Factors, Transcription, Genetic, Mutagenesis, Sequence Alignment, Genes, Reporter
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