3D Genome Organization as an Epigenetic Determinant of Transcription Regulation in T Cells

Abstract

In the heart of innate and adaptive immunity lies the proper spatiotemporal development of several immune cell lineages. Multiple studies have highlighted the necessity of epigenetic and transcriptional regulation in cell lineage specification. This mode of regulation is mediated by transcription factors and chromatin remodelers, controlling developmentally essential gene sets. The core of transcription and epigenetic regulation is formulated by different epigenetic modifications determining gene expression. Apart from "classic" epigenetic modifications, 3D chromatin architecture is also purported to exert fundamental roles in gene regulation. Chromatin conformation both facilitates cell-specific factor binding at specified regions and is in turn modified as such, acting synergistically. The interplay between global and tissue-specific protein factors dictates the epigenetic landscape of T and innate lymphoid cell (ILC) lineages. The expression of global genome organizers such as CTCF, YY1, and the cohesin complexes, closely cooperate with tissue-specific factors to exert cell type-specific gene regulation. Special AT-rich binding protein 1 (SATB1) is an important tissue-specific genome organizer and regulator controlling both long- and short-range chromatin interactions. Recent indications point to SATB1's cooperation with the aforementioned factors, linking global to tissue-specific gene regulation. Changes in 3D genome organization are of vital importance for proper cell development and function, while disruption of this mechanism can lead to severe immuno-developmental defects. Newly emerging data have inextricably linked chromatin architecture deregulation to tissue-specific pathophysiological phenotypes. The combination of these findings may shed light on the mechanisms behind pathological conditions.

Keywords: SATB1; adaptive immunity; autoimmunity; epigenetics; genome organization; thymocyte development.

Figure 1

The interplay between global and tissue-specific genome organizers and transcription factors is vital for tissue-specific gene regulation. (A) Global genome organizers (such as CTCF and the Cohesin Complex) safeguard the genomic integrity and shape the general structure of the genome, by insulating the Topologically Associating Domains (TADs) from each other. Additionally, loop extrusion within TADs facilitates long-range chromatin interactions between regulatory elements and genes. Under the control of the aforementioned global organizers and inside such sub-structures of the genome, tissue-specific transcription factors and chromatin remodeling complexes control proper spatiotemporal gene expression, during development and differentiation. (B) Global genome organizers cooperate with tissue-specific transcription factors and chromatin organizers to sustain tissue-specific transcription programs.

Figure 2

Schematic representation of SATB1 deregulation in (patho)physiology. (A) SATB1 downregulation in thymic T cells results in defective T cell training in the thymic medulla. When these self-reactive T cells circulate in the lymphatic system, they fail to recognize pathogens and instead misidentify a person’s autoantigens as hostile. This induces T cell infiltration in tissues, further accentuating inflammation observed in autoimmune phenotypes in both humans and mice. (B) SATB1 expression upregulation in normally non-expressing tissue cells is the tell-tale mark of multiple cancers. SATB1 boosts the expression of the PD1/PDL1 pathway which is responsible for both T cell senescence and exacerbating deterioration markers in cancer; namely cancer cell proliferation, differentiation, survival, and potential for metastasis.