Development of the mammalian forebrain critically depends on the dynamic but precise spatial and temporal control of gene expression. While ongoing public efforts are actively mapping gene expression patterns on a genomic scale, the transcriptional enhancer sequences that drive these exquisite patterns remain poorly defined. Comparative genomic methods increasingly enable relatively confident predictions of the location of putative distant-acting enhancers, but a deeper understanding of their exact tissue-specificities has yet to emerge due to the lack of high-quality collections of experimental datasets. In preliminary studies, we have coupled comparative genomics to a high-throughput mouse transgenic reporter assay and identified more than 100 distant-acting enhancer sequences that reproducibly drive in vivo expression in the developing forebrain and are in many cases located near genes known to be required for brain development. Here we propose to exploit this unique enhancer collection to produce a first-generation high-resolution cis-regulatory atlas of the developing forebrain. This goal will be achieved through detailed histological and neuroanatomical analysis of all forebrain enhancers identified so far. We will then bin elements that drive identical patterns within the forebrain and computationally define their common transcription factor binding sites and other sequence features and use this forebrain cis-regulatory code to generate genome-wide enhancer catalogues. The validity of such predictions will be determined through the testing of 200 of these elements in transgenic mice. High-resolution data and annotations from the initial atlas as well as enhancers generated through our predictions will be made available to the community through an existing web portal, allowing researchers to access this data to a) understand the regulation of forebrain genes, b) identify candidate regions for regulatory mutation screens in human genetic disorders, c) retrieve tissue-specific reagents for a variety of downstream experimental applications, d) download data sets for computational or experimental regulatory studies.

Public Health Relevance

Efforts to understand how genes control the development of the human brain have focused on when and where genes are active during development, but have largely ignored the role of genetic switches (""""""""enhancers"""""""") that control these very activities. Here we propose to map the precise activity of several hundred enhancers in the brain to aid in predicting additional forebrain enhancer in the entire human genome and thereby provide the scientific community with a """"""""brain enhancer atlas"""""""". These studies are likely to have implications in defining the role of these switches for normal brain function and how they go awry in human brain diseases. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS062859-01
Application #
7507860
Study Section
Special Emphasis Panel (ZRG1-MNG-K (01))
Program Officer
Mamounas, Laura
Project Start
2008-09-30
Project End
2011-08-31
Budget Start
2008-09-30
Budget End
2009-08-31
Support Year
1
Fiscal Year
2008
Total Cost
$549,631
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Genetics
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
Nord, Alex S; Pattabiraman, Kartik; Visel, Axel et al. (2015) Genomic perspectives of transcriptional regulation in forebrain development. Neuron 85:27-47
Pattabiraman, Kartik; Golonzhka, Olga; Lindtner, Susan et al. (2014) Transcriptional regulation of enhancers active in protodomains of the developing cerebral cortex. Neuron 82:989-1003
McKinsey, Gabriel L; Lindtner, Susan; Trzcinski, Brett et al. (2013) Dlx1&2-dependent expression of Zfhx1b (Sip1, Zeb2) regulates the fate switch between cortical and striatal interneurons. Neuron 77:83-98
Visel, Axel; Taher, Leila; Girgis, Hani et al. (2013) A high-resolution enhancer atlas of the developing telencephalon. Cell 152:895-908
Nord, Alex S; Blow, Matthew J; Attanasio, Catia et al. (2013) Rapid and pervasive changes in genome-wide enhancer usage during mammalian development. Cell 155:1521-31
Pennacchio, Len A; Visel, Axel (2010) Limits of sequence and functional conservation. Nat Genet 42:557-8
Visel, Axel; Blow, Matthew J; Li, Zirong et al. (2009) ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457:854-8