Many aspects of eukaryotic gene regulation resemble the regulation of bacterial operons. Both operate largely at the level of transcription, and both rely on trans-acting proteins that bind to cis-acting regulatory target sequences on the DNA molecule. These regulatory proteins determine the level of transcription from a gene by controlling the binding of RNA polymerase to the gene’s promoter.

There are three major distinguishing features of the control of transcription in eukaryotes. First, eukaryotic genes possess enhancers, which are cis-acting regulatory elements located at sometimes great linear distances from the promoter. Many genes possess multiple enhancers. Second, these enhancers are often bound by more transcription factors than are bacterial operons. Multicellular eukaryotes must generate thousands of patterns of gene expression with a limited number of regulatory proteins (transcription factors). They do so through combinatorial interactions among transcription factors. Enhanceosomes are complexes of regulatory proteins that interact in a cooperative and synergistic fashion to promote high levels of transcription through the recruitment of RNA polymerase II to the transcription start site.

Third, eukaryotic genes are packaged in chromatin. Gene activation and repression require specific modifications to chromatin. The vast majority of the tens of thousands of genes in a typical eukaryotic genome are turned off at any one time. Genes are maintained in a transcriptionally inactive state through the participation of nucleosomes, which serve to compact the chromatin and prevent the binding of RNA polymerase II. The position of nucleosomes and the extent of chromatin condensation are instructed by the pattern of post-translational modifications of the histone tails. Histone modifications are epigenetic marks that, along with the methylation of cytosine bases, can be altered by transcription factors. These factors bind to regulatory regions and recruit protein complexes that enzymatically modify adjacent nucleosomes. These large multisubunit protein complexes use the energy of ATP hydrolysis to move nucleosomes and remodel chromatin.

DNA replication faithfully copies both the DNA sequence and the chromatin structure from parent to daughter cells. Newly formed cells inherit both genetic information, inherent in the nucleotide sequence of DNA, and epigenetic information, which is in the histone code and the pattern of DNA methylation.

The existence of epigenetic phenomena such as genetic imprinting and X-chromosome inactivation demonstrates that eukaryotic gene expression can be silenced without changing the DNA sequence of the gene. Another epigenetic phenomenon, position-effect variegation, revealed the existence of repressive heterochromatic domains that are associated with highly condensed nucleosomes and contain few genes. Barrier insulators maintain the integrity of the genome by preventing the conversion of euchromatin into heterochromatin.

There is a growing appreciation for the role of functional RNAs, such as ncRNAs and miRNAs, in the regulation of eukaryotic gene expression. These RNAs serve to target protein complexes to complementary DNA or RNA in the cell. For some RNAs (like Xist), the act of transcription may tether the RNA to a chromosomal region where proteins will bind and alter chromatin. In contrast, the translation of hundreds of mRNAs is repressed when RISC bound to complementary miRNAs is targeted to their 3′ UTRs.

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