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INTRODUCTION

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OBJECTIVES

After studying this chapter, you should be able to:

  • Explain that the many steps involved in the vectorial processes of gene expression, which range from targeted modulation of gene copy number, to gene rearrangement, to transcription, to mRNA processing and transport from the nucleus, to translation, to protein subcellular compartmentalization, to posttranslational modification and degradation, are all subject to regulatory control, both positive and negative. Changes in any, or multiple of these processes, can increase or decrease the amount and/or activity of the cognate gene product.

  • Appreciate that DNA binding transcription factors, proteins that bind to specific DNA sequences that are physically linked to their target transcriptional promoter elements, can either activate or repress gene transcription.

  • Recognize that DNA binding transcription factors are often modular proteins that are composed of structurally and functionally distinct domains, which can directly or indirectly control mRNA gene transcription, either through contacts with RNA polymerase and its cofactors, or through interactions with coregulators that modulate nucleosome structure, composition and position via histone covalent modifications and/or nucleosome displacement.

  • Understand that nucleosome-directed regulatory events typically increase or decrease the accessibility of the underlying DNA such as enhancer or promoter sequences, although nucleosome modification can also create new binding sites for other coregulators.

  • Understand that the processes of gene transcription, RNA processing, and nuclear export of RNA are all coupled.

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BIOMEDICAL IMPORTANCE

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Organisms alter expression of genes in response to genetic developmental cues or programs, environmental challenges, or disease, by modulating the amount, the spatial, and/or the temporal patterns of gene expression. The mechanisms controlling gene expression have been studied in detail and often involve modulation of gene transcription. Control of transcription ultimately results from changes in the mode of interaction of specific regulatory molecules, usually proteins, with various regions of DNA in the controlled gene. Such interactions can either have a positive or negative effect on transcription. Transcription control can result in tissue-specific gene expression, and gene regulation is influenced by hormones, growth factors, heavy metals, and chemicals.

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In addition to transcription level controls, gene expression can also be modulated by gene amplification, gene rearrangement, posttranscriptional modifications, RNA stabilization, translational control, protein modification, protein compartmentalization, and protein stabilization. Many of the mechanisms that control gene expression are used to respond to developmental cues, growth factors, hormones, environmental agents, and therapeutic drugs. Dysregulation of gene expression can lead to human disease. Thus, a molecular understanding of these processes can lead to development of therapeutic agents that alter pathophysiologic mechanisms or inhibit the function or arrest the growth of pathogenic organisms.

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REGULATED EXPRESSION OF GENES IS REQUIRED FOR DEVELOPMENT, DIFFERENTIATION, & ADAPTATION

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The genetic information present in each normal somatic cell of a metazoan organism is practically identical. The genetically reproducible, hardwired exceptions are found in those few cells that have amplified or rearranged genes in order to perform specialized cellular functions. Of ...

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