Functional characterization of tissue-specific enhancers in the DLX5/6 locus
Open accessAbstract
Disruption of distaless homeobox 5 and 6 (Dlx5/6) in mice results in brain, craniofacial, genital, ear and limb defects. In humans, chromosomal aberrations in the DLX5/6 region, some of which do not encompass DLX5/6, are associated with split hand/foot malformation 1 (SHFM1) as well as intellectual disability, craniofacial anomalies and hearing loss, suggesting that the disruption of DLX5/6 regulatory elements could lead to these abnormalities. Here, we characterized enhancers in the DLX5/6 locus whose tissue-specific expression and genomic location along with previously characterized enhancers correlate with phenotypes observed in individuals with chromosomal abnormalities. By analyzing chromosomal aberrations at 7q21, we refined the minimal SHFM1 critical region and used comparative genomics to select 26 evolutionary conserved non-coding sequences in this critical region for zebrafish enhancer assays. Eight of these sequences were shown to function as brain, olfactory bulb, branchial arch, otic vesicle and fin enhancers, recapitulating dlx5a/6a expression. Using a mouse enhancer assay, several of these zebrafish enhancers showed comparable expression patterns in the branchial arch, otic vesicle, forebrain and/or limb at embryonic day 11.5. Examination of the coordinates of various chromosomal rearrangements in conjunction with the genomic location of these tissue-specific enhancers showed a correlation with the observed clinical abnormalities. Our findings suggest that chromosomal abnormalities that disrupt the function of these tissue-specific enhancers could be the cause of SHFM1 and its associated phenotypes. In addition, they highlight specific enhancers in which mutations could lead to non-syndromic hearing loss, craniofacial defects or limb malformations.
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Most families carrying mutations limited to limb-specific enhancers present SHFM1 with no other physical or mental problems, with the exception of one case of mild cognitive defects.
“Most families carrying mutations limited to the genomic region encompassing only limb-specific enhancers (Birnbaum, et al. 2012) present SHFM1 with no other physical or mental problems, with the exception of one case of mild cognitive defects.”
From <i>DLX5/6</i> GABAergic Expression Affects Social Vocalization: Implications for Human Evolution (2021) · cites this paper as Birnbaum, et al. 2012
The Discussion (page unavailable) says that disruption of tissue-specific enhancers could lead to isolated SHFM1-associated phenotypes, and the paper identifies limb enhancers in the locus. It does not report that most families with changes limited to limb-specific enhancers have SHFM1 without other problems, or identify a single exception with mild cognitive defects. (LLM, conf=0.78)
Experimental — accuracy not yet measuredDLX5/6-N-Haplotype covers the complete sequence of DLX6, the DLX5/6 intergenic region, the second intron and third exon of DLX5, three known enhancers for brain expression of DLX5/6 (I56i, I56ii, and Mef2-BA), and the three first exons of the long noncoding RNA asDLX6nc.
“The DLX5/6-N-Haplotype covers the complete sequence of DLX6, the DLX5/6 intergenic region, the second intron and third exon of DLX5, three known enhancers for brain expression of DLX5/6: I56i, I56ii, and Mef2-BA (Birnbaum, et al. 2012), and the three first exons of the long noncoding RNA asDLX6nc, which has been implicated in GABAergic neuronal differentiation (Cajigas, et al. 2018).”
From <i>DLX5/6</i> GABAergic Expression Affects Social Vocalization: Implications for Human Evolution (2021) · cites this paper as Birnbaum, et al. 2012
The Introduction (page unavailable) identifies I56i and I56ii as intergenic enhancers active in the developing forebrain. It describes the MEF2-dependent enhancer instead as regulating DLX5/6 expression in the branchial arch, so it does not support calling all three brain-expression enhancers. (LLM, conf=0.90)
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- Authors
- Birnbaum, R. Y., Everman, D. B., Murphy, K. K., Gurrieri, F., Schwartz, C. E., & Ahituv, N.
- Affiliations
- University of California, San Francisco (US)
- Greenwood Genetic Center (US)
- Università Cattolica del Sacro Cuore (IT)
- Corresponding author
- Ahituv, Nadav
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-08-21
- Volume
- 21
- Issue
- 22
- Pages
- 4930-4938
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3529576
- OpenAlex
- W2149202334
- Cited by
- 63
- References
- 58
- Citations by year
- 2025: 5 · 2024: 6 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 6 · 2018: 6 · 2017: 5 · 2016: 6 · 2015: 5 · 2014: 8 · 2013: 4
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Human Genome Research Institute (R01HG006768, R01HG005058)
- National Institute of General Medical Sciences (GM61390, U19GM061390)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090382)
- National Institute of Neurological Disorders and Stroke (R01NS079231)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD059862)
- 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 › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Keywords
- tissue-specific enhancers, non-coding regulatory elements, craniofacial defects, limb malformations, non-syndromic hearing loss, intellectual disability, olfactory bulb, otic vesicle, branchial arches, forebrain, chromosomal rearrangements
- MeSH terms
- Animals, Enhancer Elements, Genetic, Humans, Organ Specificity, Transcription Factors, Zebrafish, Homeodomain Proteins, Gene Expression Regulation, Developmental, Gene Expression Profiling, Gene Order, Proteasome Endopeptidase Complex, Mice, Comparative Genomic Hybridization, Genetic Loci
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