Transcriptional mechanisms coordinating tight junction assembly during epithelial differentiation

Abstract

Epithelial tissues form a selective barrier via direct cell-cell interactions to separate and establish concentration gradients between the different compartments of the body. Proper function and formation of this barrier rely on the establishment of distinct intercellular junction complexes. These complexes include tight junctions, adherens junctions, desmosomes, and gap junctions. The tight junction is by far the most diverse junctional complex in the epithelial barrier. Its composition varies greatly across different epithelial tissues to confer various barrier properties. Thus, epithelial cells rely on tightly regulated transcriptional mechanisms to ensure proper formation of the epithelial barrier and to achieve tight junction diversity. Here, we review different transcriptional mechanisms utilized during embryogenesis and disease development to promote tight junction assembly and maintenance of intercellular barrier integrity. We focus particularly on the Grainyhead-like transcription factors and ligand-activated nuclear hormone receptors, two central families of proteins in epithelialization.

Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4

“…In duct cells of the kidney, GRHL2 regulates lumen expansion and epithelial barrier formation by trans -activating OVOL2 expression, which in turn activates the expression of E-Cadherin, claudin 4 (epidermal tight junctions), and Rab25 (apical trafficking). 56 OVOL2 maintains the transcriptional program of human corneal epithelium cells by repressing expression of mesenchymal genes such as ZEB1 . 14 , 49 Similarly, GRHL2 is known to be a direct transcriptional repressor of ZEB1 .…”

Structural Features of Tight-Junction Proteins

“…Therefore, the expression patterns of TJ proteins in various tissues are kept under tight control by various transcription factors in addition to ZONAB. A large number of TJ and AJ transmembrane (TM) proteins are under transcriptional control by the Grainyhead-like proteins GRHL1 and GRHL2 or by nuclear receptors [144]. These transcription factors therefore regulate a large subset of proteins, making up the apical junction complex.…”

Epithelial HIF-1α/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis

“…Notably, no increase in other tight junction claudins (claudin-4 or -7), occludin, or zonula occludens-1 was observed in either HIF1A-KD or HIF1A-DN cells, despite this claudin-1-specific decrease. It is well appreciated that the regulation and interdependency or coregulation of the large family of claudin molecules is a diverse, complex, and often redundant process that is cell type and organ specific during development and homeostasis, in addition to the responses to microenvironmental cues such as inflammation or indeed hypoxia (34,35). We cannot exclude in totality potential indirect effects of CLDN1 suppression itself on other junctional molecules; however, our data support the utility of genetically and pharmacologically targeting HIF-1α to mediate attenuated esophageal inflammation in conjunction with increased claudin-1 expression in both mouse and human studies.…”