CiteULike: heliopais's enhancer

In vivo enhancer analysis of human conserved non-coding sequences

Len Pennacchio — 2006-11-06T04:08:11-00:00

Nature

Scanning Human Gene Deserts for Long-Range Enhancers

Marcelo Nobrega — 2006-08-04T00:01:53-00:00

Science, Vol. 302, No. 5644. (17 October 2003), 413.

10.1126/science.1088328

A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly

Laura Lettice — 2008-01-09T16:32:41-00:00

Hum. Mol. Genet., Vol. 12, No. 14. (15 July 2003), pp. 1725-1735.

Unequivocal identification of the full composition of a gene is made difficult by the cryptic nature of regulatory elements. Regulatory elements are notoriously difficult to locate and may reside at considerable distances from the transcription units on which they operate and, moreover, may be incorporated into the structure of neighbouring genes. The importance of regulatory mutations as the basis of human abnormalities remains obscure. Here, we show that the chromosome 7q36 associated preaxial polydactyly, a frequently observed congenital limb malformation, results from point mutations in a Shh regulatory element. Shh, normally expressed in the ZPA posteriorly in the limb bud, is expressed in an additional ectopic site at the anterior margin in mouse models of PPD. Our investigations into the basis of the ectopic Shh expression identified the enhancer element that drives normal Shh expression in the ZPA. The regulator, designated ZRS, lies within intron 5 of the Lmbr1 gene 1 Mb from the target gene Shh. The ZRS drives the early spatio-temporal expression pattern in the limb of tetrapods. Despite the morphological differences between limbs and fins, an equivalent regulatory element is found in fish. The ZRS contains point mutations that segregate with polydactyly in four unrelated families with PPD and in the Hx mouse mutant. Thus point mutations residing in long-range regulatory elements are capable of causing congenital abnormalities, and possess the capacity to modify gene activity such that a novel gamut of abnormalities is detected. 10.1093/hmg/ddg180

Genome-wide Prediction of Mammalian Enhancers Based on Analysis of Transcription-Factor Binding Affinity

Outi Hallikas — 2006-01-13T01:55:02-00:00

Cell, Vol. 124, No. 1. (13 January 2006), pp. 47-59.

SummaryUnderstanding the regulation of human gene expression requires knowledge of the "second genetic code," which consists of the binding specificities of transcription factors (TFs) and the combinatorial code by which TF binding sites are assembled to form tissue-specific enhancer elements. Using a novel high-throughput method, we determined the DNA binding specificities of GLIs 1-3, Tcf4, and c-Ets1, which mediate transcriptional responses to the Hedgehog (Hh), Wnt, and Ras/MAPK signaling pathways. To identify mammalian enhancer elements regulated by these pathways on a genomic scale, we developed a computational tool, enhancer element locator (EEL). We show that EEL can be used to identify Hh and Wnt target genes and to predict activated TFs based on changes in gene expression. Predictions validated in transgenic mouse embryos revealed the presence of multiple tissue-specific enhancers in mouse c-Myc and N-Myc genes, which has implications for organ-specific growth control and tumor-type specificity of oncogenes.

Predicting tissue-specific enhancers in the human genome.

Len Pennacchio — 2007-01-29T08:45:32-00:00

Genome Research, Vol. 17, No. 2. (8 January 2007), pp. 201-211.

Determining how transcriptional regulatory signals are encoded in vertebrate genomes is essential for understanding the origins of multicellular complexity; yet the genetic code of vertebrate gene regulation remains poorly understood. In an attempt to elucidate this code, we synergistically combined genome-wide gene-expression profiling, vertebrate genome comparisons, and transcription factor binding-site analysis to define sequence signatures characteristic of candidate tissue-specific enhancers in the human genome. We applied this strategy to microarray-based gene expression profiles from 79 human tissues and identified 7187 candidate enhancers that defined their flanking gene expression, the majority of which were located outside of known promoters. We cross-validated this method for its ability to de novo predict tissue-specific gene expression and confirmed its reliability in 57 of the 79 available human tissues, with an average precision in enhancer recognition ranging from 32% to 63% and a sensitivity of 47%. We used the sequence signatures identified by this approach to successfully assign tissue-specific predictions to approximately 328,000 human-mouse conserved noncoding elements in the human genome. By overlapping these genome-wide predictions with a data set of enhancers validated in vivo, in transgenic mice, we were able to confirm our results with a 28% sensitivity and 50% precision. These results indicate the power of combining complementary genomic data sets as an initial computational foray into a global view of tissue-specific gene regulation in vertebrates.