ConteXt of change--X inactivation and disease

Abstract

Epigenetic regulation is important for stable maintenance of cell identity. For continued function of organs and tissues, illegitimate changes in cell identity must be avoided. Failure to do so can trigger tumour development and disease. How epigenetic patterns are established during cell differentiation has been explored by studying model systems such as X inactivation. Mammals balance the X-linked gene dosage between the sexes by silencing of one of the two X chromosomes in females. This is initiated by expression of the non-coding X-inactive specific transcript (Xist) RNA and depends on specific cellular contexts, in which essential silencing factors are expressed. Normally X inactivation is initiated in early embryogenesis, but recent reports identified instances where Xist is expressed and can initiate gene repression. Here we describe the features that characterize the cellular permissivity to initiation of X inactivation and note that these can also occur in cancer cells and in specific haematopoietic progenitors. We propose that embryonic pathways for epigenetic regulation are re-established in adult progenitor cells and tumour cells. Understanding their reactivation will deepen our understanding of tumourigenesis and may be exploited for cancer therapy.

Figure 1. A schematic view of stem cell differentiation

Differentiated cells that constitute organs and tissues are generated during development. Their characteristics and identity are faithfully maintained to ensure proper organ function. Throughout life many of these cells are replenished by the differentiation of stem cells. Therefore, adult stem cells have to be maintained stably. Yet, the differentiation of stem cells requires the cell identity to be changed from a stem cell to a differentiated cell with a specialized function. This transition passes through a point when cell identity is not stable (red). Notably, during embryogenesis adult stem cells, themselves, are generated from progenitors (green arrow).

Figure 2. In mammals X inactivation compensates the difference in X-linked gene dosage between males and females

1. It is thought that the mammalian sex chromosomes X and Y originated from an autosome pair, when a spontaneous mutation arose specifying male sex (blue line). Evolution of the sex chromosomes led to the loss of sequences from the Y chromosome leading to a gene dosage difference between XY males and XX females.

2. For balancing gene dosage between the sexes random inactivation of one of the two X chromosomes in female cells is initiated by Xist (pink) and maintained by other mechanisms in differentiated cells (black).

3. Experimental expression of Xist in male cells can be used for probing the epigenetic context. In cells expressing initiation factors, Xist mediated gene silencing is initiated and loss of X-linked gene expression then causes the death of the cells. Therefore, a phenotype can be observed depending on the epigenetic context of the cell.

Figure 3. SATB1 organizes the genome for coordinate gene regulation

SATB1 forms a network that overlaps the base of chromatin loops and has been shown to recruit chromatin modifying complexes. SATB1 interacts with C-terminal binding protein 1 (CtBP1), histone deacetylase 1 (HDAC1), p300/CBP-associated factor (PCAF) and cut-like 1 (CUTL1) and colocalizes with GATA binding protein 3 (GATA3). The current view is that spatial and molecular organization of the genome is modulated by SATB1, which might be important for establishing epigenetic patterns and for coordinating gene expression.

Figure 4. Epigenetic context in tumourigenesis

1. Tumours can develop from progenitors that provide an epigenetic context for the establishment of epigenetic patterns, which can be identified by an active gene silencing pathway. Aggressive T-cell lymphomas provide an example, as they maintain properties of their T-cell progenitor origin such as SATB1 expression.

2. Other tumours are thought to establish a similar cellular context when they progress to malignant disease. Breast cancer cells provide an example for this type of tumour. When breast cancers progress to a more malignant and highly metastatic phenotype, SATB1 expression can be elevated. This might go along with a reprogramming of the tumour cell transcriptome, and albeit direct evidence is still awaited, with the re-establishment of pathways for gene silencing. In breast cancer SATB1 expression is unrelated to the cellular context from which the tumour originated and is acquired at a late stage in tumourigenesis. Establishing a progenitor-like context might endow tumour cells with developmental pathways that contribute to metastasis.