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Lentiviral single-cell MPRA of synthetic enhancers reveals motif affinity-based encoding of cell state specificity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Escherichia coli Mus musculus Homo sapiens

PROVIDER: GSE331230 | GEO | 2026/05/29

REPOSITORIES: GEO

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Lentiviral single-cell MPRA of synthetic enhancers reveals motif affinity-based encoding of cell state specificity [sc-lentiMPRA]

Project description:Cell state-specific gene expression programs emerge from the interplay between cis-regulatory elements (CREs), such as enhancers, and transcription factors (TFs). Massively parallel reporter assays (MPRAs) have enabled large-scale dissection of CRE function, but bulk approaches cannot resolve cell state specificity on continuous trajectories of cellular differentiation, and existing single-cell MPRAs are not readily applicable to primary cell differentiation models. Here, we developed a single-cell lentiviral Massively Parallel Reporter Assay (sc-lentiMPRA) that overcomes these limitations and enables parallel quantification of enhancer activity and cellular transcriptome. Applying sc-lentiMPRA in blood stem differentiation, we profiled the activity and specificity of ~160 fully synthetic enhancers with controlled motif composition and affinities across ~190,000 single cells. Focusing on Trp53 and Cebpa, we show that enhancers with high and low affinity motifs differ qualitatively and quantitatively in their responses to TF expression gradients. For Trp53, low-affinity motifs exhibited near-linear correlation with TF expression, whereas high-affinity motifs showed reduced sensitivity to TF levels and a potential contribution of cofactor availability. In contrast, Cebpa-associated enhancers displayed non-linear behaviors. Together, sc-lentiMPRA establishes a powerful framework for systematically relating enhancer architecture and TF expression to regulatory output at single-cell resolution during cellular differentiation.

2026-05-29 | GSE331072 | GEO

Lentiviral single-cell MPRA of synthetic enhancers reveals motif affinity-based encoding of cell state specificity [sc-lentiMPRA 2]

2026-05-29 | GSE331030 | GEO

Lentiviral single-cell MPRA of synthetic enhancers reveals motif affinity-based encoding of cell state specificity

Project description:Lentiviral single-cell MPRA of synthetic enhancers reveals motif affinity-based encoding of cell state specificity

| PRJNA1467519 | ENA

Lentiviral single-cell MPRA of synthetic enhancers reveals motif affinity-based encoding of cell state specificity [sc-lentiMPRA]

Project description:Lentiviral single-cell MPRA of synthetic enhancers reveals motif affinity-based encoding of cell state specificity [sc-lentiMPRA]

| PRJNA1466832 | ENA

Lentiviral single-cell MPRA of synthetic enhancers reveals motif affinity-based encoding of cell state specificity [sc-lentiMPRA 2]

Project description:Lentiviral single-cell MPRA of synthetic enhancers reveals motif affinity-based encoding of cell state specificity [sc-lentiMPRA 2]

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Cell-type-directed design of synthetic enhancers.

Project description: Not available

| S-EPMC10830415 | biostudies-literature

MprA and DosR coregulate a Mycobacterium tuberculosis virulence operon encoding Rv1813c and Rv1812c.

Project description: Not available

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A complete map of affinity and specificity encoding for a partially fuzzy protein interaction

Project description:Thousands of protein domains encoded in the human genome function by binding up to a million short linear motifs embedded in intrinsically disordered regions of other proteins. How affinity and specificity are encoded in these binding domains and the motifs themselves is not well understood. The evolvability of binding specificity - how rapidly and extensively it can change upon mutation - is also largely unexplored, as is the contribution of ‘fuzzy’ dynamic residues to affinity and specificity in protein-protein interactions. Here we produce the first global map of affinity and specificity encoding in a globular protein domain. Quantifying >200,000 energetic interactions between the domain and ligand allows us to identify 20 major energetically coupled pairs of sites. These are organised into six modules, with the vast majority of mutations in each module only reprogramming specificity for a single position in the ligand. Nine of the major energetic couplings encoding specificity are direct structural contacts and 11 have an allosteric mechanism of action. The dynamic tail of the ligand is more robust to mutation than the structured portion but contributes additively to binding affinity and communicates with structured residues to enable changes in specificity. Our results present how affinity and specificity are encoded in a globular protein domain interacting with a disordered peptide and a direct comparison of the encoding of affinity and specificity in structured and dynamic molecular recognition.

2024-04-25 | GSE265816 | GEO

High-density P300 enhancers control cell state transitions.

Project description: Not available

| S-EPMC4636788 | biostudies-literature

Motif Variation Regulates the Affinity Landscape and Epigenetic State of the MyoD Cistrome

Project description:The cis-regulatory code is the cellular lexicon by which the transcriptional machinery converts sequence information within cis-regulatory modules (CRMs) into gene expression output. Tissue-specific transcription factors such as MyoD orchestrate gene expression programs by binding to short DNA motifs called E-boxes within their target CRMs to modulate chromatin state and to fine-tune gene expression output. Despite extensive research, how the relatively short and ubiquitously distributed E-box motifs contribute to binding specificity, assembly and the functional output of the transcriptional machinery remains poorly understood. Here, we have carried out an integrative analysis of the relationship between MyoD occupancy, nucleosome positioning, CRMs-associated histone marks and motif sequences within the myogenic CRMs in differentiating muscle cells. Our data suggests that variant sequences within MyoD-binding motifs and their multiplicity within the CRMs, as well as the spatial arrangement of the motifs, in combination confer binding affinity of MyoD, nucleosome occupancy and the epigenetic state of the myogenic CRMs. Our comparative genomic analysis of single nucleotide polymorphism (SNPs) across publically available data from 17 strains of laboratory mice suggests that variant sequences within MyoD-bound motifs, but not their genome-wide counterparts, are under selection. Taken together, our data suggests that variant sequences within MyoD-binding motifs are retained and have functional role to confer a dynamic range of affinities, enabling MyoD to establish a broad spectrum of activity across myogenic CRMs.

2018-01-02 | GSE80588 | GEO

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