A regulatory module embedded in the coding region of
            <i>Hoxa2</i>
            controls expression in rhombomere 2

Tümpel, Stefan; Cambronero, Francisco; Sims, Carrie A.; Krumlauf, Robb; Wiedemann, Leanne M.

doi:10.1073/pnas.0806360105

Cited by 61 publications

(51 citation statements)

References 38 publications

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“…Given that several eExons were previously discovered to regulate the gene they reside in (Neznanov et al 1997;Lampe et al 2008;Tumpel et al 2008;Ritter et al 2012), we explicitly set out to search for coding eExons that do not autoregulate but rather could regulate their nearby genes. This was of interest to us due to the phenotypic consequences that coding mutations could have on their nearby genes.…”

Section: Resultsmentioning

confidence: 99%

“…Previous exonic enhancers (eExons) have been reported in vertebrates (Neznanov et al 1997;Lampe et al 2008;Tumpel et al 2008;Dong et al 2010;Eichenlaub and Ettwiller 2011;Ritter et al 2012). In addition, a recent study scanning for synonymous constraint in protein coding regions (Lin et al 2011) found an overlap between two of these eExons (Lampe et al 2008;Tumpel et al 2008) and synonymous constraint elements.…”

mentioning

confidence: 99%

“…In addition, a recent study scanning for synonymous constraint in protein coding regions (Lin et al 2011) found an overlap between two of these eExons (Lampe et al 2008;Tumpel et al 2008) and synonymous constraint elements. Here, we analyzed 25 available ChIP-seq data sets of enhancer marks (H3K4me1, H3K27ac, and EP300, also known as p300) for their overlap with coding exons.…”

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confidence: 99%

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Coding exons function as tissue-specific enhancers of nearby genes

Birnbaum¹,

Clowney²,

Agamy³

et al. 2012

Genome Res.

218

190

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Enhancers are essential gene regulatory elements whose alteration can lead to morphological differences between species, developmental abnormalities, and human disease. Current strategies to identify enhancers focus primarily on noncoding sequences and tend to exclude protein coding sequences. Here, we analyzed 25 available ChIP-seq data sets that identify enhancers in an unbiased manner (H3K4me1, H3K27ac, and EP300) for peaks that overlap exons. We find that, on average, 7% of all ChIPseq peaks overlap coding exons (after excluding for peaks that overlap with first exons). By using mouse and zebrafish enhancer assays, we demonstrate that several of these exonic enhancer (eExons) candidates can function as enhancers of their neighboring genes and that the exonic sequence is necessary for enhancer activity. Using ChIP, 3C, and DNA FISH, we further show that one of these exonic limb enhancers, Dync1i1 exon 15, has active enhancer marks and physically interacts with Dlx5/6 promoter regions 900 kb away. In addition, its removal by chromosomal abnormalities in humans could cause split hand and foot malformation 1 (SHFM1), a disorder associated with DLX5/6. These results demonstrate that DNA sequences can have a dual function, operating as coding exons in one tissue and enhancers of nearby gene(s) in another tissue, suggesting that phenotypes resulting from coding mutations could be caused not only by protein alteration but also by disrupting the regulation of another gene.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Coding exons function as tissue-specific enhancers of nearby genes

Birnbaum¹,

Clowney²,

Agamy³

et al. 2012

Genome Res.

218

190

View full text Add to dashboard Cite

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“…The maintenance of Hox gene expression in migrating NCCs and developing rhombomeres is regulated by independent Hox gene enhancers, sometimes resulting in expression differences between NCC subpopulations and their rhombomere of origin (Hunt et al, 1991a;Hunt et al, 1991b;Maconochie et al, 1999;Trainor and Krumlauf, 2000b;Tumpel et al, 2008;Tumpel et al, 2002). For example, the Hoxa2 expression domain has its anterior limit at the boundary between r1 and r2, whereas r2-derived NCCs migrating into PA1 are devoid of Hox gene expression (Krumlauf, 1993;Prince and Lumsden, 1994).…”

Section: Ap Patterning Of Hindbrain Nccs: the Inter-arch Hox Codementioning

confidence: 99%

Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development

2010

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SummaryDuring vertebrate craniofacial development, neural crest cells (NCCs) contribute much of the cartilage, bone and connective tissue that make up the developing head. Although the initial patterns of NCC segmentation and migration are conserved between species, the variety of vertebrate facial morphologies that exist indicates that a complex interplay occurs between intrinsic genetic NCC programs and extrinsic environmental signals during morphogenesis. Here, we review recent work that has begun to shed light on the molecular mechanisms that govern the spatiotemporal patterning of NCC-derived skeletal structures -advances that are central to understanding craniofacial development and its evolution.

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“…But, in fact, ORFs in many species simultaneously encode additional functional sequence elements within the codon sequence, often with strong evolutionary constraint on the synonymous sites Itzkovitz and Alon 2007). For example, mammalian ORFs are known to encode exonic splicing enhancers and silencers (Chen and Manley 2009), microRNA target sites (Lewis et al 2005;Hurst 2006), A-to-I recoding sites (Rueter et al 1999;Bass 2002), and transcriptional enhancers (Lang et al 2005;Nguyen et al 2007;Lampe et al 2008;Tümpel et al 2008;Dong et al 2010). Several previous studies have observed strong genome-wide trends toward increased evolutionary constraint on such overlapping functional elements, by averaging across many loci pooled together (Baek and Green 2005;Xing and Lee 2005;Chen et al 2006;Down et al 2006;Goren et al 2006;Parmley et al 2006;Robins et al 2008;Kural et al 2009).…”

mentioning

confidence: 99%

Locating protein-coding sequences under selection for additional, overlapping functions in 29 mammalian genomes

Lin¹,

Kheradpour²,

Washietl³

et al. 2011

Genome Res.

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The degeneracy of the genetic code allows protein-coding DNA and RNA sequences to simultaneously encode additional, overlapping functional elements. A sequence in which both protein-coding and additional overlapping functions have evolved under purifying selection should show increased evolutionary conservation compared to typical protein-coding genes-especially at synonymous sites. In this study, we use genome alignments of 29 placental mammals to systematically locate short regions within human ORFs that show conspicuously low estimated rates of synonymous substitution across these species. The 29-species alignment provides statistical power to locate more than 10,000 such regions with resolution down to nine-codon windows, which are found within more than a quarter of all human protein-coding genes and contaiñ 2% of their synonymous sites. We collect numerous lines of evidence that the observed synonymous constraint in these regions reflects selection on overlapping functional elements including splicing regulatory elements, dual-coding genes, RNA secondary structures, microRNA target sites, and developmental enhancers. Our results show that overlapping functional elements are common in mammalian genes, despite the vast genomic landscape.

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A regulatory module embedded in the coding region of Hoxa2 controls expression in rhombomere 2

Cited by 61 publications

References 38 publications

Coding exons function as tissue-specific enhancers of nearby genes

Coding exons function as tissue-specific enhancers of nearby genes

Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development

Locating protein-coding sequences under selection for additional, overlapping functions in 29 mammalian genomes

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