Intra- and inter-cluster regulations of multiplex gene clusters

Project Summary A gene cluster is a group of two or more homologous genes arranged within a certain genomic range. These gene clusters are widespread in genomes across species. They account for 22% and 18% of annotated genes in mice and humans, respectively. A gene family usually contains multiple gene clusters located on different chromosomes. Therefore, studying the regulation of gene clusters adds a new layer on top of traditional tran- scriptional regulation. Studies on the Keratin, Hox, Globin, Olfactory-Receptor, and other gene clusters revealed distinct epigenetic and topological states that contribute to differential transcriptional outcomes. The knowledge gaps in the field are: (i) missing detailed mechanistic machinery that constitutes specific epigenetic and topolog- ical domains on a gene cluster, (ii) is there general interchromosomal crosstalk of multiplex gene clusters in the same gene family, and (iii) what protein modules spatially organize gene clusters in the cell nucleus and facilitate their coordination. The proposed research seeks to decompose (a) epigenetic principles of gene clusters with distinct expression patterns, (b) molecular mechanisms that configure intra- and inter-cluster conformations, and (c) protein cascades that organize gene clusters within sub-nuclear structures. We will utilize the multiplex Ker- atin gene clusters as a paradigm in the biological context of avian skin development. Since gene clusters are widespread in genomes and used in novel development and organ morphogenesis, misexpression or mutation of clustered genes contributes to abnormal development and diseases. The proposed research will provide a fundamental understanding of complex gene regulation. It will also extend our previous insights of localized gene regulation to how spatial subnuclear compartmentation facilitates transcriptional heterogeneity of compound genes during tissue development and homeostasis.