Complete annotation of all functional sequences in the human genome remains a major challenge a decade after its initial sequencing. This pertains in particular to gene regulatory elements, many of which are located far away from their target genes, but play fundamental roles in human biology. Significant progress towards annotation of the gene regulatory architecture has been made in recent years predominantly using cultured human cells. However, large-scale studies in mice, as well as anecdotal examples identified in human studies, have indicated the existence of large populations of gene regulatory sequences with very restricted temporal and tissue-specific activity during mammalian development. Despite their critical importance in human development and disease, this set of regulatory sequences will likely be missed by approaches restricted to cell lines or adult tissues. To fill this gap, the major objective for this U54 application is to generate catalogs of developmentally active gene regulatory sequences using existing high throughput data production pipelines for genomic approaches including ChlP-Seq, MethylC-Seq and RNA-Seq on embryonic tissues. Performing such studies directly on human tissues is not feasible due to limited availability of human embryos at relevant stages of development. We will therefore in this study exploit the laboratory mouse, a widely used animal model that shares a similar embryonic developmental program and gene regulatory architecture with humans. In addition to embryonic development, our studies will also generate a complementary reference dataset from postnatal and adult mice to better understand the dynamics of gene regulation over time. Furthermore, we will assess the biological authenticity of identified regulatory sequences by in-depth functional validation using an established transgenic mouse pipeline. It is anticipated that generation of these datasets will fill a major void in the functional annotation o a mammalian genome and help to complete the catalog of gene regulatory sequences in the human genome.
The human genome sequence is the blueprint for the making of every cell type in the body, yet the instruction set embedded in the DNA has been poorly understood a decade after its initial sequencing. The proposed research will help the annotation of gene regulatory sequences in the human genome and contribute to understanding of the molecular basis of congenital diseases in humans.
|Preissl, Sebastian; Fang, Rongxin; Huang, Hui et al. (2018) Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation. Nat Neurosci 21:432-439|
|Osterwalder, Marco; Barozzi, Iros; Tissières, Virginie et al. (2018) Enhancer redundancy provides phenotypic robustness in mammalian development. Nature 554:239-243|
|Anderson, Courtney M; Hu, Jianxin; Thomas, Reuben et al. (2017) Cooperative activation of cardiac transcription through myocardin bridging of paired MEF2 sites. Development 144:1235-1241|
|Diao, Yarui; Fang, Rongxin; Li, Bin et al. (2017) A tiling-deletion-based genetic screen for cis-regulatory element identification in mammalian cells. Nat Methods 14:629-635|
|Yu, Miao; Ren, Bing (2017) The Three-Dimensional Organization of Mammalian Genomes. Annu Rev Cell Dev Biol 33:265-289|
|He, Yupeng; Gorkin, David U; Dickel, Diane E et al. (2017) Improved regulatory element prediction based on tissue-specific local epigenomic signatures. Proc Natl Acad Sci U S A 114:E1633-E1640|
|Gompers, Andrea L; Su-Feher, Linda; Ellegood, Jacob et al. (2017) Germline Chd8 haploinsufficiency alters brain development in mouse. Nat Neurosci 20:1062-1073|
|Turner, Tychele N; Coe, Bradley P; Dickel, Diane E et al. (2017) Genomic Patterns of De Novo Mutation in Simplex Autism. Cell 171:710-722.e12|
|Laurent, Frédéric; Girdziusaite, Ausra; Gamart, Julie et al. (2017) HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development. Cell Rep 19:1602-1613|
|Yu, Bingfei; Zhang, Kai; Milner, J Justin et al. (2017) Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation. Nat Immunol 18:573-582|
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