Effect of natural genetic variation on enhancer selection and function
Open accessAbstract
The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence to support the concept that lineage-determining transcription factors define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants.
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PU.1 can bind as a collaboration-dependent partner with NF-κB or with C/EBPα/β or IRF4/8.
“or as a collaboration-dependent partner in binding complexes, either with activation-dependent factors like NF-κB or with lineage-defining partners like C/EBPα (or β) or IRF4/8 (13–15)”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [14]
In “Variation and collaborative LDTF binding” (page not provided), the paper reports that C/EBPα motif mutations can reduce nearby PU.1 binding, supporting collaboration between those factors. In “LDTF motif mutations affect NF-κB binding” (page not provided), it instead describes NF-κB binding at sites already bound by PU.1 and/or C/EBPα; it does not establish that PU.1 binding depends on NF-κB. The supplied passages and searches do not support the specified C/EBPβ or IRF4/8 partnerships. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNatural genetic variation at enhancers is commonly observed in human populations, consistent with the relatively low sequence constraint of these regions.
“While much of the evidence for enhancer function was obtained through perturbing these regions artificially, natural genetic variation at enhancers is commonly observed in human populations, consistent with the relatively low sequence constraint of these regions [191, 192].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [192]
The section on LDTF motif mutations reports naturally occurring sequence differences in mouse enhancers and their effects on enhancer activity. The paper studies variation between mouse strains; it does not establish that enhancer variation is common in human populations or that enhancers have relatively low sequence constraint. The supplied passages and searches for human variation and sequence constraint did not substantiate those parts. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMicroglial enhancers are primed by relatively simple combinations of lineage-determining transcription factors to become sites of activity of broadly expressed signal-dependent transcription factors.
“Microglial enhancers are primed by relatively simple combinations of LDTFs (31, 32) to become sites of activity of broadly expressed signal-dependent transcription factors (SDTFs).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [32]
The locations and sequence content of enhancers provide insights into how non-coding genetic variation may affect gene expression and cellular phenotypes.
“Furthermore, the locations and sequence content of enhancers provide insights into how non-coding genetic variation may affect gene expression and cellular phenotypes (32, 36–38).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [32]
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- Authors
- Heinz, S., Romanoski, C. E., Benner, C., Allison, K. A., Kaikkonen, M. U., Orozco, L. D., & Glass, C. K.
- Affiliations
- University of California San Diego (US)
- Salk Institute for Biological Studies (US)
- University of Eastern Finland (FI)
- University of California, Los Angeles (US)
- Corresponding author
- Glass, C. K.
- Venue
- Nature
- Published
- 2013-10-13
- Volume
- 503
- Issue
- 7477
- Pages
- 487-492
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3994126
- OpenAlex
- W1982857307
- Cited by
- 298
- References
- 39
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 12 · 2023: 8 · 2022: 18 · 2021: 38 · 2020: 25 · 2019: 25 · 2018: 25 · 2017: 27 · 2016: 28 · 2015: 38 · 2014: 36 · 2013: 4
- FWCI
- 13.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R01CA173903, P30CA023100, CA17390)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, T32DK007494, DK091183, P01DK074868, P30DK063491, R01DK091183)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR059033)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- natural genetic variation, cis-regulatory elements, macrophages, inbred mouse strains, transcription factor binding, histone modifications, epigenomics, transcriptional regulation, regulatory variants, disease-associated variants
- MeSH terms
- Animals, Base Sequence, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, Histones, Macrophages, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Models, Biological, Mutation, Protein Binding, Selection, Genetic, Transcription Factors, Genetic Variation, Reproducibility of Results, NF-kappa B, Cell Lineage, Amino Acid Motifs, Mice, Transcription Factor RelA
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