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.
Highlights
X chromosome inactivation (XCI) is a paradigm to study heterochromatin formation and maintenance
X inactive specific transcript (Xist) is located on the X chromosome and it is surrounded by several other lncRNA-encoding genes, including Tsix, just proximal to Xist (Jpx), and five prime to XistT (Ftx), which, in mouse, have been shown to be involved in Xist regulation through different mechanisms, including transcriptional interference, RNA-mediated recruitment of chromatin remodelers, and through transcription co-activation [45,46,47,48]
This might be the case of subunits of the KMT2D complex; KMT2D and lysine demethylase 6A/ubiquitously transcribed tetratricopeptide repeat protein X-linked (KDM6A/UTX) mutations have been observed in patients that are affected by Kabuki Syndrome [229,230,231,232,233,234,235,236,237] and, in line with that, kmt2d knockout in zebrafish recapitulates the Kabuki phenotype and it is characterized by the deregulation of the Notch pathway [238]
Summary
Less than 2% of the genome is transcribed in protein-encoding mRNAs; most of it is actively transcribed, which suggests that a fraction produces non-coding RNAs (ncRNAs). ncRNAs are classified based on their size in small ncRNAs (200 bp, referred to as lncRNAs) [1,2]. Several studies observed defective X chromosome inactivation (XCI) in breast and basal-like cancer and linked the deregulation of the X chromosome to breast cancer (BC) [36,37,38,39,40,41,42], to ovarian cancer [43], as well as to cancers in patients affected by Klinefelter syndrome [44] This deregulation is usually given by a loss of XIST as result of disappearance of the inactive X chromosome (Xi) and amplification of the active one (Xa) [37,38,40,43,44]. Xist is located on the X chromosome and it is surrounded by several other lncRNA-encoding genes, including Tsix, just proximal to Xist (Jpx), and five prime to XistT (Ftx), which, in mouse, have been shown to be involved in Xist regulation through different mechanisms, including transcriptional interference, RNA-mediated recruitment of chromatin remodelers, and through transcription co-activation [45,46,47,48].
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