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.
|Gorkin, David U; Leung, Danny; Ren, Bing (2014) The 3D genome in transcriptional regulation and pluripotency. Cell Stem Cell 14:762-75|
|MacArthur, D G; Manolio, T A; Dimmock, D P et al. (2014) Guidelines for investigating causality of sequence variants in human disease. Nature 508:469-76|
|He, Aibin; Gu, Fei; Hu, Yong et al. (2014) Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease. Nat Commun 5:4907|
|Cheng, Yong; Ma, Zhihai; Kim, Bong-Hyun et al. (2014) Principles of regulatory information conservation between mouse and human. Nature 515:371-5|
|Attanasio, Catia; Nord, Alex S; Zhu, Yiwen et al. (2014) Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis. Genome Res 24:920-9|
|Dickel, Diane E; Zhu, Yiwen; Nord, Alex S et al. (2014) Function-based identification of mammalian enhancers using site-specific integration. Nat Methods 11:566-71|
|Gorkin, David U; Ren, Bing (2014) Genetics: Closing the distance on obesity culprits. Nature 507:309-10|
|Smallwood, Andrea; Ren, Bing (2013) Genome organization and long-range regulation of gene expression by enhancers. Curr Opin Cell Biol 25:387-94|
|Rivera, Chloe M; Ren, Bing (2013) Mapping human epigenomes. Cell 155:39-55|
|Attanasio, Catia; Nord, Alex S; Zhu, Yiwen et al. (2013) Fine tuning of craniofacial morphology by distant-acting enhancers. Science 342:1241006|
Showing the most recent 10 out of 13 publications