Role of Satb1 in the control of topological genome organization during skin development and ageing

In the era of tissue engineering and the development of novel approaches for stem cell-driven organ regeneration, it is important for researchers and physicians to understand how multi-potent stem cells differentiate into specialised cell types, and why these processes are altered during ageing and age-associated disorders, such as cancer, impaired tissue regeneration, wound healing, hair loss.

Skin serves as an important and convenient model to study the biology of ageing process, and skin structure and functions are altered during ageing. Skin also serves as a source of adult stem cells, and several distinct adult somatic cell populations isolated from the skin were successfully employed for reprogramming and generation of induced pluripotent cells.

Research into genome and chromatin biology over the last two decades has revealed that in addition to genetic mechanisms, lineage-specific gene expression programs are also regulated epigenetically, i.e., via biochemical modification of the chromatin structure.

Genome organizer Satb1 protein plays an important role in establishing specific associations between different genes in the nucleus, which are required for proper control of cellular functions and gene expression programs.

Satb1 protein regulates expression of the genes that are highly expressed in skin epithelial cells via establishing of specific three-dimensional conformation of the skin-specific genomic loci in the nucleus. However, its role in the control of skin ageing remains unclear.

In this project, we propose a systematic study to 1) understand how skin-specific gene loci are spatially organised in the nucleus, 2) define genes that form their close genomic neighbourhood and 3) understand how Satb1 protein regulates these processes during skin development and ageing.

Successful performance of this project will help in better understanding the complexity of regulatory mechanisms that control skin development and ageing and in designing new approaches for modulating ageing process and targeting stem cells in the clinical age-associated conditions accompanied by their un-controlled activation/expansion or exhausting/loss

Epigenetic mechanisms play an important role in the control of organ development and regeneration. Understanding how and why these mechanisms are altered during ageing and in many age-associated disorders (cancer, impaired wound healing, etc.) has become a growing priority in biomedical research.

Progress in the genome and chromatin biology achieved within the last two decades revealed that higher-order chromatin remodelling and establishment of specific long-range arrangements of the genes from the same or different chromosomes in three-dimensional nuclear space are important for proper control of cell differentiation and organ development.

In this proposal, we will use a complex approach including 4C chromatin conformation capture technology, 3D-FISH and genetically modified mouse models to test a hypothesis that the genomic neighbourhood of lineage-specific genes is functionally important for proper execution of differentiation programs in epidermal progenitor cells and that genome organizer Satb1 regulates the establishment and remodelling of such neighbourhoods in keratinocytes during development, postnatal growth and ageing.

This project will address two Specific Aims:

1. Define the basic principles that control the organisation of the genomic neighbourhood of lineage-specific gene loci in epidermal keratinocytes and its functional significance during normal development, postnatal growth and ageing.

2. Define the role of genome organizer Satb1 in the establishment of distinct genomic neighbourhoods for lineage-specific gene loci in epidermal keratinocytes during development and its remodelling during ageing.

This project will help in better understanding the complexity of regulatory mechanisms that control development and ageing, as well as in designing new approaches on how to modulate skin ageing by targeting Satb1 and correcting age-associated alterations of gene expression programs in keratinocytes.

Knowledge of the mechanisms regulating organ development is important to understanding the changes in organ regenerative capacity which occur during ageing and age-associated disorders, such as impaired wound healing and malignancy.

SCIENTIFIC COMMUNITY
This project will provide substantial new knowledge for the scientific community and will contribute to an advance in public health benefits.
Delineating the functions of Satb1 in skin development and ageing will help to advance knowledge for investigators working in the following areas of fundamental research (developmental biology, molecular biology, stem cell biology and tissue regeneration, hair follicle biology), in addition to clinical (dermatology, gerontology) and veterinary medicine.

PUBLIC HEALTH & AWARENESS
This project will have significant health implications and will benefit the public sector, including health professionals and their patients. There is an ever-increasing incidence of age-associated disorders within the UK and also within other countries. Information generated by this project will provide new opportunities for therapeutic interventions to cure ageing-associated skin pathologies, including chronic epithelial wounds, skin cancers, specific forms of hair loss, which ultimately contributes to the enhancement of quality of life.

INDUSTRY
The pharmaceutical, cosmetic and food industries will all benefit from this project via advancement of the knowledge of molecular mechanisms controlling skin regeneration and ageing, which is clearly required for the development of new approaches to improve diagnosis and for treatment of diabetic wounds and age-associated skin pathological conditions. Knowledge transfer activity with the industrial partners will be actively implemented for those areas of the results that can be used for new therapeutic product development. The new generated knowledge will also be used in relevant higher education courses for basic scientists and health professionals.

Overall, this project will provide information of substantial importance for researchers, the business/industrial sector, and health professionals within the NHS, whilst longer term will contribute to better public health.