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.
Highlights
Introduction reports identified instances whereX-inactive-specific transcript (Xist) is expressed and can initiate gene repression
Current research into epigenetic of X inactivation and note that these can occur in cancer cells and in specific mechanisms aims at an understanding how the genome is regulated in development and disease
The severity of symptoms arising from mutations of the X-linked methyl CpG binding protein 2 (MeCP2) gene in female RETT patients has been observed to correlate with the pattern of X inactivation
Summary
In addition to PcG genes, other components of chromatin remodelling complexes have been associated with diseases such as X-linked alpha-thalassemia with mental retardation (ATR-X syndrome) which is caused by mutations in the SWI/ SNF (Switch/Sucrose NonFermentable) homologue 2 (SNF2) chromatin remodelling protein Alpha thalassemia/mental retardation syndrome X-linked (ATRX) (Gibbons et al, 1995) These examples illustrate that understanding the basic principles of chromatin biology is of immediate relevance for a variety of human diseases. Non-random patterns of X inactivation lead to phenotypic variability in a number of human diseases associated with mutations on one of the two X chromosomes in female patients. The severity of symptoms arising from mutations of the X-linked MeCP2 gene in female RETT patients has been observed to correlate with the pattern of X inactivation (reviewed in Chahrour & Zoghbi, 2007). Mutations that affect non-randomness do not appear to necessarily overlap with the disease causing mutation
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