| Περίληψη: | <p>Thymic epithelial cells (TECs) uniquely have broad transcriptional ability to express
over 90% of all protein-coding genes, including those which are tissue-restricted,
through a process referred to as promiscuous gene expression (PGE). PGE is in part
under the control of the autoimmune regulator (AIRE) in TECs, although the precise
molecular mechanisms by which AIRE operates to enable PGE, are not fully
understood. Chromodomain helicase DNA binding protein 6 (CHD6) is a DNAdependent ATPase, which plays a role in chromatin remodeling, and it has been
proposed as one of the AIRE partners. The overall aim of this doctoral thesis is to define
and understand the role of CHD6 in thymus biology. A mouse model, which is
conditionally deficient of CHD6 in TECs (designated as <em>Chd6<sup>TEC-/-</sup></em>
), was generated to
investigate the proposed objective. Phenotypic analyses of <em>Chd6<sup>TEC-/-</sup></em> mice
demonstrated no differences in the qualitative and quantitative measures of TECs,
thymocytes and peripheral T cells compartment, indicating non-essential role of CHD6
in the development of thymic epithelial cells and thymocytes maturation in general.
Interestingly, genome-wide transcriptomic data and analysis of tissue-specific-antigen
in TECs revealed that CHD6 is a positive regulator of PGE, predominantly among
genes decorated with repressive histone marks. CHD6 is proposed to regulate PGE by:
i) localising and recruiting AIRE protein complexes to specific loci possessing DNA
strand breaks and decorated with specific repressive histone marks, and ii) changing
the chromatin accessibility of the particular loci. Confocal imaging confirmed the
physical proximity of CHD6 and AIRE in medullary TEC which corroborates the
proposed functional interaction. Additionally, <em>Chd6<sup>TEC-/-</sup></em> mice are observed to be more
susceptible to organ-specific-autoimmunity. In summary, this study has demonstrated
CHD6 as a novel regulator of PGE and its crucial role in central tolerance induction.
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