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CHAPTER 5 - BINDING

D:  BINDING AND THE
CONTROL OF GENE TRANSCRIPTION

BIOCHEMISTRY - DR. JAKUBOWSKI

Last Updated: 03/30/16

Learning Goals/Objectives for Chapter 5D:  After class and this reading, students will be able to

  • describe general mechanisms of how a gene for a given protein might be negatively and positively regulated at the level of gene transcription;
  • describe the structure/function/role of promoters, response elements, RNA polymerase, transcription factors, nucleosomes, histone proteins, epigenetic modifications of DNA in gene transcription;
  • explain the differences (structural, Kds) between specific and nonspecific binding of a ligand to a macromolecule, at the structural level;
  • describe the structural features of both proteins and DNA that result in specific and nonspecific binding;
  • describe and give examples of how post-translational modifications of proteins and epigenetic modifications of DNA can alter gene expression;
  • explain how the apparent Kd for a protein binding to DNA can be altered by the presence of another protein bound to DNA at a proximal site
  • describe the basis of RNA interference in gene expression

D16.  Eukaryotic Species Complexity

The increasing complexity of eukaryotic organisms was thought to arise from an increasing number of genes.  This simplistic assumptions has not been validated from the results of sequencing and annotating the genomes of many eukaryotic organisms.  Compare these statistics:  the number of putative genes in the simple nematode round worm C. Elegans, the fruit fly drosophila, and the human are approximately 20,000, 14,000, and about 23,000.  There seems to be little correlation of species complexity with number of genes.  Other possible mechanisms for increasing complexity from a given genome size include producing different proteins from the same genes through differential splicing of RNA transcripts and rearranging DNA as occurs in immune cells to produce the huge repertoire of possible antibody molecules necessary for recognition of nonself molecules (such as viruses and bacteria).  These mechanisms can not account for the incredible complexity of the human species.  Levine and Tjian have proposed two other mechanisms that could account for increasing complexity.  Complexity would arise from the number of gene expression patterns and involve the involvement of nonprotein-coding regions of the genome, which in humans accounts for up to 98% of the genome.  One mechanism requires the present of greater number and complexity of DNA regulatory sequences (enhancers, silencers, promoters) in more complex organisms.  Since these sequences are in the DNA (the molecule that is transcribed), they are called cis-regulatory sequences.  The second mechanism involves an increase in the  elaboration and complexity of proteins (trans-regulatory elements) that regulate gene expression in more complex organisms..  These proteins could include transcription factors, proteins interacting with enhancer sequences, and proteins involved in chromatin remodeling (described above).  They estimate that up to a third of the human genome (1 billion base pairs) might be involved in the regulation of gene transcription.  In addition, 5-10% of all proteins expressed from genes appear to regulate gene transcription.  There appears to be about  300, 1000, and 3000  transcription factor in yeast, drosophila and C. elegans, and humans, respectively.  There is about one transcription factor for every gene in yeast, but one for every ten in humans. 

In simple eukaryotes, cis regulatory elements would include the promoter (TATA box region), and upstream regulatory sequences (enhancer) and silencers about 100-200 base pairs from the promoter.  In more complex eukaryotic species like humans,  the promoter is more complex, containing the TATA box, initiator sequences (INR) and downstream promoter elements (DPE).  Upstream cis regulatory elements (as far as 10 kb from the promoter) include multiple enhancers, silencers, and insulators.  Most promoters have TATA boxes, where TATA Binding Protein (TBP) binds.  Upstreams elements in turn regulate the binding of TBP. 

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