forensic zinc (4).docx - locus is highly decorated with the...

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locus is highly decorated with the repressive H3K27me3 catalyzed by EZH2 in epidermal stem cells. Then, during epidermal differentiation, H3K27me3 is removed by the KDM6B (JMJD3) histone demethylase. Loss of this control over programmed p16 expression occurs in epithelial cancers, such as squamous cell carcinoma (SCC), where EZH2 is overexpressed and KDM6B expression is lost. In the breast, progesterone can lead to increased levels of EZH2 to promote mammary epithelial cell proliferation. However, excessive EZH2 expression occurs in breast cancers, exemplifying how epigenetics can integrate environmental signals and have a profound influence on the fine balance between stem cell maintenance and overt carcinogenesis. Indeed, loss of key chromatin regulation that promotes cell differentiation, and gain of activities that promote stemness, is a recurrent theme in cancer. Chromatin modifying enzymes also play a major role in influencing cell type specificity. High levels of EZH2 that modify H3K27me3 promote adipogenesis while simultaneously inhibiting osteogenesis. In contrast, the H3K27me3 demethylases, KDM6A (UTX) and KDM6B (JMJD3), derepress those same genes, driving stem cells toward osteogenesis. Through interactions with tissue-
specific master regulators, epigenetic modifiers also shape cell type specificity. In the epidermis, p63, the p53 family member that is a master regulator of the epidermal compartment, interacts with several chromatin regulators including HDAC1 and HDAC2,

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