Gene Regulation In Metazoans

The evolution of animal bodies composed of different cell types required mechanisms for turning gene expression on and off in specific cells at particular times during development. The temporal and spatial dimensions of animal development, the thousands of genes in animal genomes, the tendency for the same gene product

I should like to work like the archaeologist who pieces together the fragments of a lovely thing which are alone left to him. As he proceeds, fragment by fragment, he is guided by the conviction that these fragments are part of a larger whole which, however, he does not yet know

—Hans Spemann Embryonic Development and Induction (1938)

Several genetic steps seem to be interposed between the reception of a signal, extrinsic to the genome, and its translation first into genetic and later into developmental terms. A hierarchy of genes may be involved in this process . . .

—Antonio Garcia-Bellido (1975)

Coactivator

Coactivator

Figure 3.1

Gene regulation in metazoans

Figure 3.1

Gene regulation in metazoans

The transcription of genes is regulated by transcription factors that bind to c/s-regulatory DNA sequences. Transcriptional activators (TF) recruit coactivators that open the local chromatin through an associated acetylase activity. Repressors can act through corepressors that have an associated deacetylase activity. RNA polymerase II has many associated transcription factors that are involved in forming an active transcription complex on the promoter, immediately upstream of the site at which transcription is initiated.

to be utilized in different ways at multiple stages of development, and the packaging of metazoan genes within chromatin (a complex of DNA with many associated proteins in cell nuclei) require more complicated regulatory mechanisms to achieve the independent control of individual genes than the mechanisms typically found in unicellular organisms or viruses.

Both the protein machinery involved in transcription to produce messenger RNAs (mRNAs) and the structure of genes at the DNA level are more complicated in metazoans than in prokaryotes. Activation of tissue-specific gene expression requires the assembly of protein complexes involving at least three components (Fig. 3.1):

• RNA polymerase II and its associated general transcription factors

• Cell-specific, tissue-specific, field-specific, or signal transducer-type activators

• Coactivators that make contacts between activators and the general transcription machinery and influence the local state of chromatin

Importantly, gene regulation is not all about activation. The spatial and temporal specificity of gene expression depends a great deal on specific repressors that act to suppress transcription, often through corepressors that affect the local state of chromatin. Many of the genes in the toolkit for animal development are transcriptional activators or repressors.

The general transcription machinery is assembled on DNA sequences called promoters, which are found near the site of the start of transcription. Activators and repressors bind to other DNA sequences to affect the transcriptional activity of the gene. Sometimes, these sites may be located in the vicinity of the promoter regions. Often, however, the regulatory proteins that mediate the transcriptional activity of individual developmentally regulated genes bind to specific sites in discrete DNA regions, called cis-regulatory elements (or czs-elements), which can influence the level of transcription by several orders of magnitude, from sites that may be many thousands of base-pairs away from the promoter. The modularity of these elements is illustrated by their ability to regulate transcription of essentially any gene in cis. Such ci's-elements are usually identified and their function studied by analyzing their activity in regulating a heterologous reporter gene (Fig. 3.2). For example, they may regulate transcription through the looping of distant sequences that brings bound activators and coactiv-ators in contact with the transcription initiation complex at the promoter; they may also act by affecting the state of chromatin (Fig. 3.1).

The expression of individual genes at particular stages and locations in the developing animal is often controlled by ci's-elements that are distinct from those controlling gene expression at other times and places. Thus metazoan genes not only consist of the coding sequences for a particular protein, but also often possess a modular array of ci's-elements that act as genetic switches to control gene expression in a variety of different contexts. The modularity of metazoan cis-regulatory DNA is critical both to the specificity of gene interactions during development and to evolutionary changes in gene expression during the evolution of new morphologies.

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