Systematic discovery of regulatory motifs in conserved regions of the human genome, including thousands of CTCF insulator sites
Open accessAbstract
Conserved noncoding elements (CNEs) constitute the majority of sequences under purifying selection in the human genome, yet their function remains largely unknown. Experimental evidence suggests that many of these elements play regulatory roles, but little is known about regulatory motifs contained within them. Here we describe a systematic approach to discover and characterize regulatory motifs within mammalian CNEs by searching for long motifs (12–22 nt) with significant enrichment in CNEs and studying their biochemical and genomic properties. Our analysis identifies 233 long motifs (LMs), matching a total of ≈60,000 conserved instances across the human genome. These motifs include 16 previously known regulatory elements, such as the histone 3′-UTR motif and the neuron-restrictive silencer element, as well as striking examples of novel functional elements. The most highly enriched motif (LM1) corresponds to the X-box motif known from yeast and nematode. We show that it is bound by the RFX1 protein and identify thousands of conserved motif instances, suggesting a broad role for the RFX family in gene regulation. A second group of motifs (LM2*) does not match any previously known motif. We demonstrate by biochemical and computational methods that it defines a binding site for the CTCF protein, which is involved in insulator function to limit the spread of gene activation. We identify nearly 15,000 conserved sites that likely serve as insulators, and we show that nearby genes separated by predicted CTCF sites show markedly reduced correlation in gene expression. These sites may thus partition the human genome into domains of expression.
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Divergent gene pairs separated by CTCF sites had lower than expected correlation of gene expression genome-wide, confirming the insulatory role of CTCF on the global scale.
“and it was found that divergent gene pairs separated by CTCF sites had lower than expected correlation of gene expression genome-wide, confirming the insulatory role of CTCF on the global scale [327].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [327]
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- Authors
- Xie, X., Mikkelsen, T. S., Gnirke, A., Lindblad-Toh, K., Kellis, M., & Lander, E. S.
- Affiliations
- Broad Institute (US)
- Broad Institute of MIT and Harvard, Massachusetts Institute of Technology and Harvard Medical School, Cambridge, MA 02142;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-04-24
- Volume
- 104
- Issue
- 17
- Pages
- 7145-7150
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1852749
- OpenAlex
- W2011457803
- Cited by
- 305
- References
- 2
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 7 · 2023: 6 · 2022: 8 · 2021: 4 · 2020: 7 · 2019: 12 · 2018: 9 · 2017: 9 · 2016: 12 · 2015: 11 · 2014: 20 · 2013: 20 · 2012: 28
- FWCI
- 16.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Broad Institute
- National Human Genome Research Institute (R01HG004037)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- conserved non-coding elements, regulatory motifs, RFX1, gene expression regulation, gene expression correlation, neuron-restrictive silencer element, human genome, chromatin domains
- MeSH terms
- Regulatory Factor X Transcription Factors, Regulatory Factor X1, CCCTC-Binding Factor, Base Sequence, Binding Sites, DNA-Binding Proteins, Humans, Molecular Sequence Data, Repressor Proteins, Species Specificity, Transcription Factors, Genome, Human, Conserved Sequence, Insulator Elements
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