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Lecture 1

BIOLOGY 1A03 Lecture 1: Biology Theme 3 Module 3

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Alastair Tracey

Biology Theme 3 Module 3 Unit 1: Cellular Differentiation All the cells in our body are derived from a single fertilized egg. At one point, as a zygote, all of your embryonic stem cells were identical. Early embryonic stem cells have an almost unlimited ability to mature or differentiate into the many different cell types in the body. As a result, as adults, our bodies contain around 200 distinct cells types. How is it that a single celled zygote is able to develop into a multicellular eukaryotic organism in this manner? This is an especially intriguing question, as most of the different cells contain the exact same genetic information. From the final divisions that occur in early developmental cascades, cells are able to communicate with each other, and begin to engage in various genetic interactions that will regulate not only continual development, but also cellular differentiation. Development of a eukaryotic organism from a single fertilized zygote is dependent on the molecular communication between cells. Different embryonic cells will have different fates depending on the signals that are exchanged and which genes are switched on or off at specific times. This is the case with the development of a frog as seen in these images. In the cluster of cells that make up an early frog embryo (top), signals travel across membranes to control gene transcription and the embryo's overall development (bottom right). Gene regulation is responsible for creating various cells types in multicellular organisms. Despite carrying the same genome, specific cells within multicellular organisms, can be organized into groups of cells or sometimes tissue types that can work together to carry out specific functions. That is, even though they have the same genome, gene regulation differences will lead to altered proteomes, which contributes to distinct differences in cellular functions. For example, our red blood cells, hepatocytes, muscle cells, neurons and epithelial cells all have very distinct functions. These cells all developed from the same embryonic stem cells, but these cells were specialized and committed to their final cell lineage based on different cues or signals that were received during embryonic development. The variation in specialized cell types are largely dependent on the differentiation that occurred from common stem cells during the early developmental cascade. Transcription factors are proteins that bind to specific sequences in DNA. They contain certain structures that allow them to interact with the DNA double helix and so control the transcription of DNA to RNA, and contribute to gene regulation. Throughout development, from a fertilized egg, transcription factors play essential roles in determining the pathway that a specific cell type will follow and will determine the final mature or differentiated cell type that will form. It is the specific gene expression patterns that are triggered within dividing embryonic stem cells, in addition to extracellular cues that leads to the diverse array of specialized cells that develop in our bodies. Transcription factors often work in concert with other proteins that can result in various changes in gene expression during successive cell divisions as cells mature throughout development. By controlling which genes are active along the chromosome, this leads to the vast array of cell types that are found throughout our bodies. As a result, certain proteins can be found only in specific cell types, or their relative amounts can vary from cell to cell. Unit 2: Chromatin Remodeling Transcriptional regulation in prokaryotes and eukaryotes is fundamentally similar. For example, both prokaryotes and eukaryotes have proteins that are involved with activating and repressing transcription, and both utilize RNA polymerase to bind to promoters that are upstream of genes to initiate transcription, but this is much more complex in eukaryotes. The differences can be attributed to the organizational differences between prokaryotic and eukaryotic genomes. We saw with the prokaryotic genome that groups of related genes with similar functions can often be found clustered together into operons transcribed by a single promoter. This is different from eukaryotes in which each gene is controlled by its own promoters and enhancers. Also, as we previously learned, DNA in eukaryotes is organized into highly compacted chromatin. While the compacting of DNA into tightly wound chromatin fibers makes for an easy way to fit all the DNA within the nucleus and also allows for DNA to be moved around during cell division, the winding of DNA in nucleosomes can affect whether DNA is transcribed or not. Genes within this tightly wound heterochromatin are usually not expressed. To be able to transcribe a specific gene product, it is necessary to unwind the DNA. Within eukaryotic DNA, we find that the DNA is tightly wound around a complex of histone proteins, forming the nucleosome structure. Each nucleosome contains an octamer of 8 histone proteins around which approximately 150 DNA base pairs wrap around. When DNA is tightly wound into chromatin, the DNA is not accessible due to the tight winding around the histone proteins. As a result, the chromatin must unravel in order for transcription to occur. This is accomplished through the process of chromatin remodeling. Part of chromatin remodeling begins when an activator protein or transcription factor is able to bind to an accessible enhancer site. This leads to the further recruitment of other proteins that can lead to further chromatin remodeling. Transcriptional regulation is highly dependent on being able to reveal the important DNA sequences that are important for transcription. Since DNA is tightly wound around histone proteins, transcription requires changes to chromatin structure to enable transcription factors to bind important DNA regions, recruit RNA polymerase, and facilitate the transcriptional process. DNA is tightly wound around histone proteins due to the interactions of the positively charged tails of histone proteins with the negatively charged phosphates in DNA. During the chromatin remodeling process, activator proteins can recruit the co-activator enzyme histone acetyl transferase (or HAT) which can attach acetyl groups to lysine amino acids along the positively charged tails of nucleosome histone proteins. When these tails are acetylated, the positive charge is reduced, and the interaction between the histones and the wound DNA is weakened. As a result, this loosening or unwinding of heterochromatin now permits transcription factors to be able to bind to previously unavailable DNA sequences that are important for transcription. In addition to acetylation, other chemical modifications can include methylation of lysine and arginine and phosphorylation of serine and threonine amino acids along the histone protein tails. These modifications may also alter the charges of these tails and can therefore alter their binding to the DNA that is wound around them, allowing space for transcriptional proteins to work. The end result is the modification of strings of amino acids that protrude from histone proteins. The degree of modifications to the histone tails is part of a histone code that determines whether transcription is activated or repressed. For example, acetylation and methylation with a single methyl group allows for transcriptional activation (represented by the + symbol), while methylation with three methyl groups leads to repression of transcription. Unit 3: Regulating Eukaryotic Transcription Once tightly wound chromatin has been unwound transcription factors (or trans- acting factors) are able to regulate eukaryotic transcription. Many transcription factors are able to recognize and bind to nucleic acid sequences in DNA based on structural and chemical complementarity between the proteins and DNA. Based on previous research on the structural features of various DNA binding regulatory proteins, most transcription factors can be classified based on the structures of their distinct DNA binding motifs. These DNA binding motifs include the basic helix-loop- helix, helix-turn-helix, zinc finger and leucine zipper regions. Most of these transcription factors have alpha-helical domains that tend to fit nicely within the major grooves of DNA. This can occur due to molecular interactions (such as hydrogen bonds) that can occur between the amino acids in the alpha helix and the functional groups of the nitrogenous bases along the major grooves of the DNA. When a strong enough interaction is made, then the transcription factor assumes a conformation that allows for the control of transcription. This can include recruitment of other transcription factors, RNA polymerase and finally activation of transcription at the target gene. In eukaryotes, specific DNA sequences (or cis-sequences) are required to initiate transcription. These are the specific promoter regions. The TATA box and transcriptional start sites form par
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