The development of human brain is an immensely complex process, which is likely reflected in the complexity of the underlying transcriptional processes. Gene expression and its precise spatio-temporal regulation, particularly by histone modifications and non-coding RNAs, are crucial for normal human brain development and are thought to be altered in major developmental psychiatric disorders, such as autism spectrum disorders (ASD). Moreover, changes in the developmental brain transcriptome are likely the major contributors to the evolution of the most distinctly human aspects of cognition, some of which are also affected in ASD and other psychiatric disorders However, our understanding of transcriptional and epigenetic processes involved in the development, evolution and dysfunction of the human brain is still elusive. Furthermore, most of our knowledge of transcriptional processes in the human brain is limited to the expression of protein coding genes. Given that the genomes of humans and other mammals have approximately the same protein-coding complexity, there is likely an additional reservoir of transcriptional complexity, especially in organs such as the brain, which has many structurally and functionally distinct regions in humans. This view is corroborated by recent findings of the ENCODE consortium, which found many cis-acting regulatory regions and that 60% of the human genome is transcribed, with a majority of the transcripts belonging to non-coding RNAs. Moreover, these and other studies have also uncovered pervasive involvement of regulatory DNA variations in common human diseases and evolution. However, how these findings on non-coding elements in cell lines relate to the complexity of human brain development and dysfunction is still largely unknown. The objective of this proposal is to employ unbiased and genome-wide approaches to (1) discover and characterize developmentally regulated and human-specific non-coding functional genomic elements in multiple regions of the developing human and non-human primate brains, (2) and elucidate their role(s) in the molecular pathophysiology of ASD, by using genomic analyses of post-mortem ASD brains, by screening for de novo mutations in ASD quartets, and by modeling functional consequences of ASD-associated elements in the developing mouse brain.

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Non-coding functional genomic elements play a crucial role in normal human brain development by regulating gene transcription. These elements are thought to be altered in major developmental psychiatric and neurological disorders. Thus, the identification and functional characterization of non-coding elements in human neurodevelopment may lead to development of new and more effective treatments of major brain disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZMH1-ERB-C (03))
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Senthil, Geetha
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Yale University
Schools of Medicine
New Haven
United States
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Onorati, Marco; Li, Zhen; Liu, Fuchen et al. (2016) Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. Cell Rep 16:2576-92
Won, Hyejung; de la Torre-Ubieta, Luis; Stein, Jason L et al. (2016) Chromosome conformation elucidates regulatory relationships in developing human brain. Nature 538:523-527
Olmos-Serrano, Jose Luis; Kang, Hyo Jung; Tyler, William A et al. (2016) Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination. Neuron 89:1208-22
Kawasawa, Yuka Imamura; Salzberg, Anna C; Li, Mingfeng et al. (2016) RNA-seq analysis of developing olfactory bulb projection neurons. Mol Cell Neurosci 74:78-86
Caubit, Xavier; Gubellini, Paolo; Andrieux, Joris et al. (2016) TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons. Nat Genet 48:1359-1369
Silbereis, John C; Pochareddy, Sirisha; Zhu, Ying et al. (2016) The Cellular and Molecular Landscapes of the Developing Human Central Nervous System. Neuron 89:248-68
D'Gama, Alissa M; Pochareddy, Sirisha; Li, Mingfeng et al. (2015) Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. Neuron 88:910-7
Shibata, Mikihito; Gulden, Forrest O; Sestan, Nenad (2015) From trans to cis: transcriptional regulatory networks in neocortical development. Trends Genet 31:77-87
Willsey, A Jeremy; State, Matthew W (2015) Autism spectrum disorders: from genes to neurobiology. Curr Opin Neurobiol 30:92-9
PsychENCODE Consortium; Akbarian, Schahram; Liu, Chunyu et al. (2015) The PsychENCODE project. Nat Neurosci 18:1707-12