Genetics: Gene Expression

Gene expression is controlled at multiple levels, including transcription (initiation and elongation), posttranscriptional processing, RNA stability, RNA export and association with ribosomes, translation (initiation and elongation), and posttranslational processing. Each level tends to be highly regulated and complex. Moreover, each level requires the cooperation of both general and cell-type-specific proteins.

Just as phenotypic differences among species are due to differences in the genes encoded by their genomes, differences among cell types within an organism are largely due to differences with which genes within a genome are transcribed. The genomes of multicellular organisms contain genes that are transcribed in all or most cell types, as well as genes whose transcription is confined to specific cells. From the earliest stages of embryogenesis, transcription is confined to only certain segments of the genome, depending on the cell type and stage of development. Thus, cellular differentiation—the process by which cells acquire and maintain specialized functions—generally entails the differential activation and repression of gene transcription. Differential gene transcription is generally regulated at two broad levels.

Control by transcriptional activators and repressors. All genes are transcribed by the transcription machinery, which consists of a large protein complex. The basal transcription complex contains the core proteins needed to recognize promoter sequences, unwind the DNA duplex, and initiate, elongate, and terminate the primary transcript. This complex also contains proteins that recognize certain types of DNA damage and can recruit proteins to repair the transcribed DNA strand. The basal transcription complex interacts with a large number of specific transcriptional activators and repressors (transcription factors)—regulatory proteins that bind elements outside the immediate promoter region. These regulatory proteins, then, dictate whether or not the basal transcription complex initiates transcription.

Some cells express highly specialized transcription factors that regulate the expression of genes confined to that cell type or its precursors. For example, muscle cells express specific factors that control the transcription of genes encoding muscle-specific proteins. Although these transcription factors can stimulate muscle-specific gene transcription in some nonmuscle cells (e.g., fibroblasts), they cannot activate muscle-specific gene transcription in many other cell types. Moreover, some cell-type-specific genes are controlled by transcription factors that are expressed by many different cell types. Thus, the presence of specific transcriptional activators and repressors alone is generally insufficient for cell-type-specific gene transcription. In addition to the presence of specific transcription factors, the target genes must be in an accessible chromatin state.

Control by chromatin state and epigenetic inheritance. In general, genes located within heterochromatin are inaccessible to the transcriptional machinery, and thus are not expressed, despite the presence of specific transcriptional activators. Such genes are said to be silenced in order to distinguish them from unexpressed genes in euchromatin. Unexpressed genes in euchromatin remain accessible to the transcriptional machinery, and thus can readily respond to physiological or environmental signals. Silenced genes, by contrast, cannot respond to external signals unless the signal includes one to remodel the chromatin (that is, reset the boundaries of heterochromatin and euchromatin). Whether a DNA segment is heterochromatic or euchromatic is generally determined during embryogenesis. The mechanisms that control the state of chromatin are incompletely understood. They include reversible changes to the DNA, such as methylation of cytosine, as well as reversible changes to chromatin proteins, such as acetylation of histones.

The state of chromatin is an important mechanism for initiating and maintaining differential gene expression in multicellular organisms. In adult organisms, the state of the chromatin is generally stably and faithfully maintained, even though chromatin-associated proteins are transiently stripped from the DNA during the processes of replication or repair. Thus, once the pattern of chromatin is established in a differentiated cell, it is stably inherited from one cell generation to the next. This form of inheritance is termed epigenetic inheritance, since it does not entail irreversible changes to genomic DNA.