Axel Visel

Scientist, Genomics Division

Lawrence Berkeley National Laboratory
MS84-171
1 Cyclotron Rd
Berkeley, CA 94720

Phone: 1-510-495-2301
Fax: 1-510-486-4229

e-mail: avisel at lbl dot gov

Axel




Research Interests

The sequence of the human genome has been known for nearly a decade, but well-defined functional annotations exist mainly for the small portion of the genome that encodes proteins. In sharp contrast, the 98% non-coding regions of the genome remain poorly annotated. Individual examples from gene-centric studies have provided strong evidence that the non-coding portion of the genome harbors distant-acting transcriptional enhancers and have shown that these regulatory sequences are critical for normal embryonic development. Human genetic studies also identified examples of human disease caused by perturbed enhancer sequences. However, systematic identification and functional characterization of distant-acting enhancers in the human genome proved to present a formidable challenge for several reasons:
  • In contrast to the genetic code of proteins, the sequence features of enhancers are poorly understood, prohibiting their reliable computational identification in the human genome.
  • Transcriptional enhancers can act over long distances (hundreds of thousands of basepairs) and can be located upstream, downstream or in introns of protein-coding genes. Their genomic position can therefore not be easily inferred from the known position and structure of a protein-coding gene.
  • Many genes are surrounded by complex arrays of regulatory elements with distinct and/or partially redundant activities.
  • The in vivo activity patterns of regulatory elements cannot be reliably predicted by computational methods and generally transgenic reporter assays are required to define when and where a particular regulatory sequence is active during development or in adult organs.
  • Some epigenetic features and molecular marks of regulatory sequences including enhancers have been identified through in vitro chromatin studies, yet it remains unclear how these insights can be leveraged to provide functional annotations of in vivo activities of human regulatory sequences.
We are interested in combining comparative genomics, sequencing-based chromatin studies (ChIP-seq), and transgenic reporter assays to identify and characterize distant-acting transcriptional enhancers at a genomic scale. These studies provide genome-wide predictions of sequences that are likely to be enhancers, as well as experimental evidence for the in vivo function of subsets of these enhancer candidates. Our efforts focus in particular on the generation of experimental datasets that will be useful to elucidate fundamental mechanisms of development (e.g. forebrain, heart and craniofacial development) and reveal regulatory sequences that are relevant for related forms of human disease.



Publications

Visel A*, Blow MJ*, Li Z, Zhang T, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Wright C, Chen F, Afzal V, Ren B, Rubin EM, Pennacchio LA. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 2009, 457:854-858. PubMed Data Sets
Visel A, Akiyama JA, Shoukry M, Afzal V, Rubin EM, Pennacchio LA. Functional autonomy of distant-acting human enhancers. Genomics 2009, Epub ahead of print. PubMed
Visel A, Prabhakar S, Akiyama JA, Shoukry M, Lewis KD, Holt A, Plajzer-Frick I, Afzal V, Rubin EM, Pennacchio LA. Ultraconservation identifies a small subset of extremely constrained developmental enhancers. Nature Genet 2008, 40:158-60. PubMed Data Sets
Prabhakar S, Visel A, Akiyama JA, Shoukry M, Lewis KD, Holt A, Plajzer-Frick I, Morrison H, Fitzpatrick DR, Afzal V, Pennacchio LA, Rubin EM, Noonan JP. Human-specific gain of function in a developmental enhancer. Science 2008, 312:1346-50. PubMed
Rahimov F, Marazita ML, Visel A, ..., Murray JC (23 authors). Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip. Nature Genet 2008, 40:1341-7. PubMed
De Val S, Chi NC, Meadows SM, Minovitsky S, Anderson JP, Harris IS, Ehlers ML, Agarwal P, Visel A, Xu SM, Pennacchio LA, Dubchak I, Krieg PA, Stainier DY, Black BL. Combinatorial regulation of endothelial gene expression by ets and forkhead transcription factors. Cell 2008, 135:1053-64. PubMed
Moldrich RX, Laine J, Visel A, Beart PM, Laffaire J, Rossier J, Potier MC. Tmem50b (C21orf4), a candidate for Down syndrome neurophenotypes, encodes an intracellular membrane protein expressed in the rodent brain. Neuroscience 2008, 154(4):1255-1266. PubMed
Visel A, Carson J, Oldekamp J, Warnecke M, Jakubcakova V, Zhou X, Shaw CA, Alvarez-Bolado G, Eichele G. Regulatory Pathway Analysis by High-Throughput In Situ Hybridization. PLoS Genet 2007, 3(10):e234. PubMed Full Text Small PDF Large PDF
Ahituv N, Zhu Y, Visel A, Holt A, Afzal V, Pennacchio LA, Rubin EM. Deletion of ultraconserved elements yields viable mice. PLoS Biol 2007, 5(9):e234. PubMed Full Text Small PDF Large PDF
Visel A, Bristow J, Pennacchio LA. Enhancer identification through comparative genomics. Semin Cell Dev Biol 2007, 18(1):140-52. PubMed
Lein ES, Hawrylycz MJ, ..., Visel A, ..., Jones AR (108 authors). Genome-wide atlas of gene expression in the adult mouse brain. Nature 2007, 445(7124):168-76. PubMed
Visel A, Minovitsky S, Dubchak I, Pennacchio LA. VISTA Enhancer Browser--a database of tissue-specific human enhancers. Nucleic Acids Res 2007, 35:D88-92. PubMed Full Text Small PDF Large PDF
Pennacchio LA, Ahituv N, Moses AM, Prabhakar S, Nobrega MA, Shoukry M, Minovitsky S, Dubchak I, Holt A, Lewis KD, Plajzer-Frick I, Akiyama J, De Val S, Afzal V, Black BL, Couronne O, Eisen MB, Visel A, Rubin EM. In vivo enhancer analysis of human conserved non-coding sequences. Nature 2006, 444(7118):499-502. PubMed
Visel A, Alvarez-Bolado G, Thaller C, Eichele G. Comprehensive analysis of the expression patterns of the adenylate cyclase gene family in the developing and adult mouse brain. J Comp Neurol 2006, 496(5):684-97. PubMed
Yaylaoglu MB, Titmus A, Visel A, Alvarez-Bolado G, Thaller C, Eichele G. Comprehensive expression atlas of fibroblast growth factors and their receptors generated by a novel robotic in situ hybridization platform. Dev Dyn 2005, 234(2):371-86. PubMed Full Text PDF
Schumacher S, Laass K, Kant S, Shi Y, Visel A, Gruber AD, Kotlyarov A, Gaestel M. Scaffolding by ERK3 regulates MK5 in development. EMBO J 2004, 23(24):4770-9. PubMed Full Text PDF
Plas DT, Visel A, Gonzalez E, She WC, Crair MC. Adenylate Cyclase 1 dependent refinement of retinotopic maps in the mouse. Vision Res 2004, 44(28):3357-64. PubMed
Danilova N, Visel A, Willett CE, Steiner LA. Expression of the winged helix/forkhead gene, foxn4, during zebrafish development. Dev Brain Res 2004, 153(1):115-9. PubMed
Visel A, Thaller C, Eichele G. GenePaint.org: an atlas of gene expression patterns in the mouse embryo. Nucleic Acids Res 2004, 32:D552-6. PubMed Full Text PDF
Herzig U, Cadenas C, Sieckmann F, Sierralta W, Thaller C, Visel A, Eichele G. Development of high-throughput tools to unravel the complexity of gene expression patterns in the mammalian brain. Novartis Found Symp 2001, 239:129-46. PubMed




Links

Databases

VISTA Enhancer Browser - activity of conserved developmental enhancers in transgenic mouse embryos at e11.5
Genepaint.org - ISH-based expression atlas of the e14.5 mouse embryo
Allen Brain Atlas - Genome-wide ISH-based high-resolution expression atlas of the adult mouse brain

last edited Feb 2009