Academic journal article Genetics

Stable Binding of the Conserved Transcription Factor Grainy Head to Its Target Genes throughout Drosophila Melanogaster Development

Academic journal article Genetics

Stable Binding of the Conserved Transcription Factor Grainy Head to Its Target Genes throughout Drosophila Melanogaster Development

Article excerpt

TO understand how developmental processes are controlled, and how, when perturbed, they can lead to disease, it is crucial to determine the mechanisms by which transcription factors interact with the DNA to regulate gene expression. Broadly expressed transcription factors can regulate multiple, distinct developmental processes, but whether they do so through context-specific DNA-binding events, or through activities subsequent to DNA binding, remains an open question. Based on the relatively limited number of studies that have elucidated transcription factor binding over multiple stages of development, it has been suggested that functional binding events are temporally dynamic (Jakobsen et al. 2007; Zinzen et al. 2009; Wilczynski and Furlong 2010; Spitz and Furlong 2012; Yanez-Cuna et al. 2012; Slattery et al. 2013, 2014). These changes in binding site occupancy by sequence-specific transcription factors are regulated largely through alterations in chromatin structure that modulate the accessible regions of the genome (Kaplan et al. 2011; Li et al. 2011). Nonetheless, factors that act at the top of gene regulatory networks may have pioneering activity, marking cis-regulatory regions, and remaining bound to DNA in multiple developmental contexts (Spitz and Furlong 2012; Iwafuchi-Doi and Zaret 2014; Slattery et al. 2014). To begin to explore the mechanisms by which widely expressed transcription factors can regulate a variety of developmental processes, we focused on the deeply conserved transcription factor Grainy head (Grh), which is a master regulator of epithelial cell fate.

Epithelial tissues are sheets of tightly bound cells that contribute to multiple structures in adult and developing organisms, including the epidermis and lining of the digestive tract, blood vessels, lungs, and ducts. The Grh-family of proteins is an essential regulator of epithelial morphogenesis in metazoans ranging from worms to humans (Wang and Samakovlis 2012). There are three Grh family members in mammals, GRHL1, GRHL2 and GRHL3, which are necessary for neural tube closure during normal vertebrate development, and for wound healing following injury (Ting et al. 2005a,b; Gustavsson et al 2008; Rifat et al 2010). In Drosophila melanogaster, where Grh was first identified, the Grh family is represented by a single grh gene (Bray et al. 1988, 1989; Bray and Kafatos 1991). Similarly to its mammalian homologs, the grh gene in Drosophila is essential for embryonic development and wound healing (Bray and Kafatos 1991; Mace etal. 2005). Further highlighting the vast degree of conservation among Grh-family members, Grh proteins from worms to flies to humans bind to a shared sequence motif through a DNA-binding domain that is unique to the related Grh and CP2 protein families (Venkatesan et al. 2003). In Drosophila, Grh has been implicated in a large number of processes in addition to wound healing, including tracheal tube formation and neural stem cell differentiation (Hemphala et al. 2003; Cenci and Gould 2005; Narasimha et al. 2008; Baumgardt et al. 2009). For most of these processes, however, the direct transcriptional targets of Grh remain unknown. Thus, Drosophila Grh provides a powerful system from which to elucidate whether a broadly expressed, master regulator of differentiation influences a large number of diverse processes through temporally dynamic DNA binding, or through a regulated activity subsequent to DNA binding.

By focusing on a deeply conserved, regulator of cell fate, we also provide insight into how epithelial cells are specified in a diversity of organisms, and how misregulation can lead to disease. Morphogenic processes during embryonic development require that cells transition between epithelial and mesenchymal cell fates (Lim and Thiery 2012). During this transition, epithelial cells lose their differentiated characteristics, such as cell-cell adhesion and cell polarity, and gain the properties of mesenchymal cells, including motility, invasiveness, and resistance to apoptosis (Hay 1995; Mani et al. …

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