Role of the genome organizer SATB1 in salivary gland maturation and regeneration

About This Grant

Project Summary There are no viable long-term treatments for salivary gland (SG) dysfunction and degeneration as a result of disease or chronic injury, driving a need for new, translatable solutions. SG dysfunction severely compromises the oral health and quality of life of patients: saliva protects the oral mucosa, facilitates articulation and food digestion, and aids in the remineralization of dental hard tissues. Therapeutic ionizing radiation (IR) for head and neck cancer where SGs are inadvertently irradiated along with the tumor (~50,000 cases/year) is a prime source of dry mouth (xerostomia). To develop treatment strategies for this detrimental injury, it is essential to understand the mechanisms that control the generation and regeneration of the SG. Generation of SG from stem cells transplanted into the tissue (now in clinical trials) offers great benefit for patients with severe loss of glandular tissue and has often utilized developmental strategies. However, the ability to produce the specific cell lineages necessary for long-term function remains poorly understood. Although we and others have made great inroads into regenerating the existing salivary tissue after IR induced damage, an outcome we have achieved through the application of synthetic muscarinic agonist (cevimeline), much more is needed to restore the tissue to a healthy state. For this purpose, we propose to focus on a genome organizer protein, SATB1, that acts to establish three-dimensional chromatin architecture, recruiting transcription and epigenetic factors to specific gene loci, and regulate cell type-specific expression of a large cohort of genes. Our preliminary studies show critical roles of SATB1 in the establishment of acinar cells and cellular architecture during postnatal maturation of submandibular glands (SMGs), highlighting it as a potential regulator of lineage specification. Our preliminary data also support a role for SATB1 in DNA repair and induction of Satb1 expression post-IR. Based on these results taken together, we hypothesize that SATB1 plays a fundamental role in generating and regenerating SMG epithelial cell lineages after injury. We will address our central hypothesis via two specific aims: Aim 1, Determine how SATB1 regulates chromatin architecture and gene expression during SG postnatal development, and Aim 2, Investigate SATB1’s role in SG maturation and regeneration after injury. These aims will be achieved using a combination of developmental and regenerative mouse models in conjunction with transcriptomic, epigenetic, biochemical, and high-resolution imaging techniques. We envisage our findings will greatly contribute to our understanding of the critical factors promoting the generation/regeneration of SG that can then be targeted for development of effective long-term therapies.