In vivo enhancer analysis of human conserved non-coding sequences
Open accessAbstract
Identifying the sequences that direct the spatial and temporal expression of genes and defining their function in vivo remains a significant challenge in the annotation of vertebrate genomes. One major obstacle is the lack of experimentally validated training sets. In this study, we made use of extreme evolutionary sequence conservation as a filter to identify putative gene regulatory elements, and characterized the in vivo enhancer activity of a large group of non-coding elements in the human genome that are conserved in human-pufferfish, Takifugu (Fugu) rubripes, or ultraconserved in human-mouse-rat. We tested 167 of these extremely conserved sequences in a transgenic mouse enhancer assay. Here we report that 45% of these sequences functioned reproducibly as tissue-specific enhancers of gene expression at embryonic day 11.5. While directing expression in a broad range of anatomical structures in the embryo, the majority of the 75 enhancers directed expression to various regions of the developing nervous system. We identified sequence signatures enriched in a subset of these elements that targeted forebrain expression, and used these features to rank all approximately 3,100 non-coding elements in the human genome that are conserved between human and Fugu. The testing of the top predictions in transgenic mice resulted in a threefold enrichment for sequences with forebrain enhancer activity. These data dramatically expand the catalogue of human gene enhancers that have been characterized in vivo, and illustrate the utility of such training sets for a variety of biological applications, including decoding the regulatory vocabulary of the human genome.
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Not all distal conserved elements are detectably enhancers, and far more of the gene-distal non-coding genome is annotated as a regulatory element than is conserved.
“Not all distal conserved elements are detectably enhancers39 and far more of the gene-distal non-coding genome is annotated as a regulatory element than is conserved60,104.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [39]
Evolutionary conservation can support the functional candidacy of a region, but not all enhancers are conserved.
“Evolutionary conservation can support the functional candidacy of a region39, but not all enhancers are conserved123-125126.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [39]
Comparative genomic methods have identified putative conserved cis-regulatory elements or regulatory RNAs, a disproportionate number of which are proposed to regulate human brain-expressed genes.
“Comparative genomic methods have been applied by several groups (Lindblad-Toh et al., 2011; Margulies et al., 2007; Pennacchio et al., 2006; Pollard et al., 2006; Prabhakar et al., 2006; Siepel et al., 2005) to identify putative conserved CREs or regulatory RNAs, a disproportionate number of which are proposed to regulate human brain-expressed genes (Johnson et al., 2009; Pennacchio et al., 2006;”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Pennacchio et al., 2006
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- Authors
- Pennacchio, L. A., Ahituv, N., Moses, A. M., Prabhakar, S., Nobrega, M. A., Shoukry, M., Minovitsky, S., Dubchak, I., Holt, A., Lewis, K. D., Plajzer-Frick, I., Akiyama, J., De Val, S., Afzal, V., Black, B. L., Couronne, O., Eisen, M. B., Visel, A., & Rubin, E. M.
- Affiliations
- Lawrence Berkeley National Laboratory (US)
- University of California, San Francisco (US)
- Corresponding author
- Pennacchio, Len A.
- ORCID
- Venue
- Nature
- Published
- 2006-11
- Volume
- 444
- Issue
- 7118
- Pages
- 499-502
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1996760543
- Cited by
- 1,165
- References
- 2
- Citations by year
- 2026: 23 · 2025: 25 · 2024: 34 · 2023: 34 · 2022: 24 · 2021: 48 · 2020: 50 · 2019: 44 · 2018: 50 · 2017: 51 · 2016: 66 · 2015: 67 · 2014: 74 · 2013: 73 · 2012: 97
- FWCI
- 35.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.osti.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- University of North Texas Digital Library (University of North Texas) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- enhancers, conserved non-coding elements, ultraconserved elements, tissue-specific enhancers, embryonic gene expression, brain development, gene regulatory elements, enhancer prediction
- MeSH terms
- Animals, Base Sequence, Chromosomes, Human, Pair 16, Embryo, Mammalian, Embryo, Nonmammalian, Enhancer Elements, Genetic, Humans, Mice, Transgenic, Nervous System, Transcription Factors, Gene Expression, Genome, Human, Prosencephalon, Conserved Sequence, Genomics, Takifugu, Mice
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