Key Concepts of Section 9.7

• Epigenetic control of transcription refers to repression or activation that is maintained after cells replicate as the result of DNA methylation or post-translational modification of histones, especially histone methylation.

• Methylation of CpG sequences in CpG island promoters in mammals generates binding sites for a family of methyl-binding proteins (MBDs) that associate with histone deacetylases, inducing hypoacetylation of the promoter regions and transcriptional repression.

• Histone H3 lysine 9 di- and trimethylation creates binding sites for the heterochromatin-associated protein HP1, which results in the condensation of chromatin and transcriptional repression. These post-translational modifications are perpetuated following chromosome replication because the methylated histones are randomly associated with the daughter DNA molecules and associate with histone H3 lysine 9 methyl transferases that methylate histone 3 lysine 9 on newly synthesized histone octamers assembled on the daughter DNA.

• Polycomb complexes maintain repression of genes initially repressed by sequence-specific repressors expressed early during embryogenesis. One class of Polycomb repressive complexes, PRC2 complexes, associates with these repressors in early embryonic cells, resulting in methylation of histone H3 lysine 27. This methylation creates binding sites for subunits in the PRC2 complex as well as for PRC1 complexes, which condense chromatin, inhibit the assembly of preinitiation complexes, and inhibit elongation. Since parent histone octamers with H3 methylated at lysine 27 are distributed to both daughter DNA molecules following DNA replication, PRC2 complexes that associate with these nucleosomes maintain histone H3 lysine 27 methylation through cell division.

• Trithorax complexes oppose repression by Polycomb complexes by methylating H3 at lysine 4 and maintaining this activating mark through chromosome replication.

• X-chromosome inactivation in female mammals requires a long noncoding RNA (lncRNA) called Xist that is transcribed from the X-inactivation center of one X chromosome and then spreads by a poorly understood mechanism along the length of the same chromosome. Xist interacts with a co-repressor that binds a histone deacetylase and PRC2 complexes at an early stage of embryogenesis, initiating X inactivation. X inactivation is maintained throughout the remainder of embryogenesis and adult life by continued association with Polycomb complexes and DNA methylation of CpG island promoters on the inactive X.

• Some lncRNAs have been discovered that lead to repression of genes in trans, as opposed to the cis inactivation imposed by Xist. Repression is initiated by their interaction with PRC2 complexes.

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  Some lncRNAs are associated with gene activation. Much remains to be learned about how lncRNAs are targeted to specific chromosomal regions, but the discovery of about 15,000 nuclear lncRNAs expressed in specific types of human cells during specific stages of their differentiation suggests that lncRNAs are central to widely used mechanisms of transcription regulation.