Genome organiser Satb1 and the control of tissue-specific chromatin remodelling during regeneration of the epidermis

With major progress being made in tissue engineering and organ regeneration, it is important to understand how the expression of genes in stem cells leads to their development into specialised cell types. Skin epithelium is a self-renewing biological structure that consists of the stem cells residing in the basal layer and differentiating into keratinocytes of suprabasal layers. This process results in a formation of an epidermal barrier protecting organisms from harmful environmental factors and is accompanied by activation of a number of epidermis-specific genes, located in the genome as clusters on four distinct chromosomes. However, it is unclear how these clusters are distributed in the nuclei of epidermal cells and what regulates their intra-nuclear arrangements and activity.
We will test whether this process is regulated by a specific Satb1 protein that intergrates remodeling of large chromatin domains with regulation of gene expression.
This project will shed light on the mechanisms that control gene reorganisation in the nuclei of epidermal cells and will be useful for better understanding the principles of stem cell-driven organ regeneration. Success of this project will be important for the progress in establishing new approaches in stem cell-based therapy and regenerative medicine.

During development and regeneration, multi-potent progenitor cells establish tissue-specific programs of gene expression that underlie a process of their differentiation into specialized cell types. Evidence accumulated in recent years suggests that high-order chromatin organization, spatial arrangement of genes within the nuclear space, as well as nuclear compartmentalization of chromatin-remodeling complexes and transcription machinery play an important role in controlling gene expression.

Genome organiser Satb1 protein plays a fundamental role in the execution of tissue-specific gene expression programs integrating the high-order chromatin architecture with regulation of gene expression. Satb1 controls high-order chromatin remodelling of a number of tissue-specific gene loci (e.g., MHC class-I locus, TH2 cytokine locus, beta-globin locus) and promote their conformational changes required for the targeting chromatin remodelling enzymes and transcription factors into transcriptionally active chromatin loops.

Here, we propose to study a role of Satb1 in the establishment of tissue-specific gene expression programs in epithelial progenitor cells in the developing and regenerating skin. We will test a hypothesis that Satb1 plays an essential role in establishing tissue-specific chromatin organisation in multi-potent progenitor cells required for proper execution of gene expression programs in the developing and regenerating skin epithelium.

We will address this hypothesis by asking: 1) whether the loss or gain of the Satb1 activity will alter three-dimensional chromatin organization and gene expression programs in keratinocytes and affect normal epidermal development and self-renewing capacity in vivo; 2) whether Satb1 regulates chromatin remodelling and the regeneration-associated gene expression programs in epidermal progenitor cells during wound healing.

Successful realisation of this proposal will provide an important background for further analyses of mechanisms that control high-order chromatin remodelling during the execution of gene expression programmes in multi-potent stem cells inside and outside the skin. This study will also be important for the development of new approaches to modulate stem cell activity in normal skin and in pathological conditions associated with stem cell expansion (carcinogenesis, hyper-proliferative skin disorders) or loss (altered wound healing, hair loss, etc.).