Spatial Polarity of Human Genes within Nuclei and Its Relationship to Cellular Organization

Garza-Gongora, Arturo

doi:https://doi.org/10.21985/n2-cx94-3k14

Work

Spatial Polarity of Human Genes within Nuclei and Its Relationship to Cellular Organization

Public

Download PDF

Download All Files (.zip)

The blueprint of life is contained within the sequence of an organism’s genome. While virtually all cells of an individual multicellular eukaryotic organism contain a near identical code of nucleic acid sequences, an organism must give rise to and maintain a varied set of cells and phenotypes. As such, sequence alone does not explain the functional outcome of building life. The cells of an organism carry out a diverse set of functions by spatiotemporally regulating gene expression. It has long been understood that histone modifications and chromatin compaction can affect the permissibility of transcription of any one gene. Nuclear organization and the compartmentalization of DNA within the nucleus are emerging as important regulators in establishing patterns of gene expression. In particular, the radial distribution of genes and chromosomes has been shown to have a defined pattern, with active transcription and gene rich chromosomes occupying the nuclear interior, and gene poor chromosomes and silenced, developmentally regulated gene loci positioned at the nuclear periphery. Furthermore, DNA can spatially associate with nuclear activity “hotspots”, such as those that occur in nuclear bodies, to facilitate nuclear processes. However, the nucleus is inextricably tied to the cell in which it resides, and a long-standing question that remains to be determined is whether the subnuclear localization of gene loci is related to the extra-nuclear activity in the rest of the cell. Here, using a model of epidermal differentiation as a model of cell polarity, we test the hypothesis that the spatial localization of genes is related to the cellular localization of their encoded proteins. We find that genes that encode components of hemidesmosomes (HDs) are spatially polarized in the nucleus towards the sites of their proteins in organotypic raft cultures that recapitulate epidermal differentiation and in migrating keratinocytes. We also demonstrate that gene polarity within the nucleus impacts the asymmetric distribution of HD mRNAs in the cytoplasm. Furthermore, we find that disruption of the interaction with the extracellular substrate and perturbation of the linker of nucleoskeleton and cytoskeleton (LINC) complex results in the coincident loss of polarized HD gene positioning and distribution of their encoded protein and mRNA. Our results indicate that spatial genome organization and cellular organization are inherently intertwined, and that nuclear gene polarity plays an important role in establishing tissue asymmetry and cell identity.

Creator