In Vivo Enhancer Analysis Chromosome 16 Conserved NoncodingSequences

Pennacchio, Len A.; Ahituv, Nadav; Moses, Alan M.; Nobrega, Marcelo; Prabhakar, Shyam; Shoukry, Malak; Minovitsky, Simon; Visel, Axel; Dubchak, Inna; Holt, Amy; Lewis, Keith D.; Plajzer-Frick, Ingrid; Akiyama, Jennifer; De Val, Sarah; Afzal, Veena; Black, Brian L.; Couronne, Olivier; Eisen, Michael B.; Rubin, Edward M.

doi:10.1038/nature05295

Title: In Vivo Enhancer Analysis Chromosome 16 Conserved NoncodingSequences

Journal Article · Wed Feb 01 00:00:00 EST 2006 · Nature

DOI:https://doi.org/10.1038/nature05295· OSTI ID:919760

Pennacchio, Len A.; Ahituv, Nadav; Moses, Alan M.; Nobrega, Marcelo; Prabhakar, Shyam; Shoukry, Malak; Minovitsky, Simon; Visel, Axel; Dubchak, Inna; Holt, Amy; Lewis, Keith D.; Plajzer-Frick, Ingrid; Akiyama, Jennifer; De Val, Sarah; Afzal, Veena; Black, Brian L.; Couronne, Olivier; Eisen, Michael B.; Rubin, Edward M.

The identification of enhancers with predicted specificitiesin vertebrate genomes remains a significant challenge that is hampered bya lack of experimentally validated training sets. In this study, weleveraged extreme evolutionary sequence conservation as a filter toidentify putative gene regulatory elements and characterized the in vivoenhancer activity of human-fish conserved and ultraconserved1 noncodingelements on human chromosome 16 as well as such elements from elsewherein the genome. We initially tested 165 of these extremely conservedsequences in a transgenic mouse enhancer assay and observed that 48percent (79/165) functioned reproducibly as tissue-specific enhancers ofgene expression at embryonic day 11.5. While driving expression in abroad range of anatomical structures in the embryo, the majority of the79 enhancers drove expression in various regions of the developingnervous system. Studying a set of DNA elements that specifically droveforebrain expression, we identified DNA signatures specifically enrichedin these elements and used these parameters to rank all ~;3,400human-fugu conserved noncoding elements in the human genome. The testingof the top predictions in transgenic mice resulted in a three-foldenrichment for sequences with forebrain enhancer activity. These datadramatically expand the catalogue of in vivo-characterized human geneenhancers and illustrate the future utility of such training sets for avariety of iological applications including decoding the regulatoryvocabulary of the human genome.

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Research Organization:: Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Director, Office of Science; National Institutes ofHealth

DOE Contract Number:: DE-AC02-05CH11231; NIHHL066681

OSTI ID:: 919760

Report Number(s):: LBNL-59842; R&D Project: GHPG6B; BnR: 400412000; TRN: US200822%%524

Journal Information:: Nature, Vol. 444, Issue 7118; Related Information: Journal Publication Date: 11/23/2006

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
CHROMOSOMES
DNA
GENES
HUMAN CHROMOSOME 16
IN VIVO
NERVOUS SYSTEM
TESTING
TRAINING
TRANSGENIC MICE
VERTEBRATES
In Vivo Enhancer Chromosome 16

Title: In Vivo Enhancer Analysis Chromosome 16 Conserved NoncodingSequences

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