Chromatin Regulator SPEN/SHARP in X Inactivation and Disease.

Abstract

Simple SummaryCarcinogenesis is a multistep process involving not only the activation of oncogenes and disabling tumor suppressor genes, but also epigenetic modulation of gene expression. X chromosome inactivation (XCI) is a paradigm to study heterochromatin formation and maintenance. The double dosage of X chromosomal genes in female mammals is incompatible with early development. XCI is an excellent model system for understanding the establishment of facultative heterochromatin initiated by the expression of a 17,000 nt long non-coding RNA, known as X inactive specific transcript (Xist), on the X chromosome. This review focuses on the molecular mechanisms of how epigenetic modulators act in a step-wise manner to establish facultative heterochromatin, and we put these in the context of cancer biology and disease. An in depth understanding of XCI will allow a better characterization of particular types of cancer and hopefully facilitate the development of novel epigenetic therapies.Enzymes, such as histone methyltransferases and demethylases, histone acetyltransferases and deacetylases, and DNA methyltransferases are known as epigenetic modifiers that are often implicated in tumorigenesis and disease. One of the best-studied chromatin-based mechanism is X chromosome inactivation (XCI), a process that establishes facultative heterochromatin on only one X chromosome in females and establishes the right dosage of gene expression. The specificity factor for this process is the long non-coding RNA X inactive specific transcript (Xist), which is upregulated from one X chromosome in female cells. Subsequently, Xist is bound by the corepressor SHARP/SPEN, recruiting and/or activating histone deacetylases (HDACs), leading to the loss of active chromatin marks such as H3K27ac. In addition, polycomb complexes PRC1 and PRC2 establish wide-spread accumulation of H3K27me3 and H2AK119ub1 chromatin marks. The lack of active marks and establishment of repressive marks set the stage for DNA methyltransferases (DNMTs) to stably silence the X chromosome. Here, we will review the recent advances in understanding the molecular mechanisms of how heterochromatin formation is established and put this into the context of carcinogenesis and disease.