Eukaryotic Gene Regulation

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1 Eukaryotic Gene Regulation
AP Biology Campbell Biology Sections

2 Steps of Genetic Expression
Genetic Expression is a multi- step pathway Expression requires that each step take place The rate of activity at each step in the pathway is variable, which means that each step provides an opportunity for genetic control and regulation

3 Histones and DNA Condensation
DNA may exist in either a condensed form or an extended form Condensation involves the formation of “nucleosomes”. A nucleosome consists of a few wraps of DNA around a set of 8 proteins called Histones As discussed in our unit on Cell Division, the extended form is generally referred to as Chromatin The Chromatin form is less bulky and tends to be visibly amorphous (no distinct visible form) Transcription requires that DNA be extended. Condensed DNA cannot be expressed

4 Histones and DNA Condensation
Note that the Histones are not simple clumps of protein Each molecule of Histone has a “tail” When chromosomes condense, these Histone tails interact These interactions will determine how tightly adjacent nucleosomes will condense.

5 Histones and DNA Condensation
The Histone tails contain the amino acid Lysine, which has a charged side chain. This charged region causes tails from adjacent nucleosomes to attract each other, promoting tighter condensation The addition of an “acetyl” group to the lysine in the tails will remove the charged regions The result is looser condensation

6 Heterochromatin Acetylation promotes Extension of the chromatin by interfering with the interaction of histone tails. Transcription requires that DNA is extended Acetylation is a significant first step towards promoting Transcription

7 Methylation vs Acetylation
The addition of Methyl groups to Histone tails promotes Condensation Condensed chromatin cannot be transcribed The addition of Acetyl groups to histone tails promotes Extension Extended chromatin can be transcribed

8 Histone Methylation vs DNA Methylation
The addition of a methyl group to the nucleotide Cytosine will also tend to prevent transcription of genes, but by a different mechanism than methylation of the Histone tails DNA methylation has a much longer term effect than histone methylation

9 Methylation and Epigenetics
Methylation of Histone tails inhibits transcription by promoting chromatin condensation This effect is temporary Methylation of cytosine in the actual DNA molecule inhibits transcription by a different mechanism DNA methylation is long-term It is an extremely important factor in embryonic development It has profound influence on the health of individuals Methylated DNA in gametes tends to be inherited, so it will also affect the development and health of offspring

10 Moshe Szyf Moshe Szyf is a professor of Pharmacology and Therapeutics at McGill University in Montreal, Quebec, Canada Dr. Szyf is a pioneer in the understanding of Epigenetics, especially the role of DNA methylation in genetic regulation The video is a Ted Talk given in July of 2016 How Early Life Experience is Written into DNA _szyf_how_early_life_experience_is _written_into_dna

11 Nadine Burke Harris Nadine Burke Harris is the Surgeon General of California Her video is a Ted Talk from February of 2015 Her emphasis in this Ted Talk is more about Trauma and Health than it is about DNA, but the underlying perspective is still Methylation of DNA has profound health significance It depends greatly on environmental exposure, including “adverse childhood experience” It is heritable How Childhood Trauma Affects Health Across a Lifetime ?v=95ovIJ3dsNk

12 Enhancers, Activators and Promoters
In both prokaryotes and eukaryotes there are control elements associated with genes that have an effect on the transcription of those genes The Promoter region is the area upstream of the gene where the RNA polymerase binds to begin transcription

13 Enhancers, Activators and Promoters
Eukaryotes have two different sets of control elements, one near the promoter (proximal) and one that may be several thousand base pairs upstream (distal) The distal control elements, or “Enhancers” will bind proteins that serve as activators for transcription

14 The Transcription Initiation Complex
The enzyme that actually transcribes the gene is RNA polymerase To transcribe, the polymerase needs to bind to the promoter region In Eukaryotes, the binding of the polymerase involves a series of other proteins (including Activator proteins) Each of these proteins binds at a particular region of the DNA, some near the promoter (proximal) and some far upstream (distal)

15 Some Vocab Clarification
DNA Regions Enzymes and Regulatory Proteins Gene Includes Introns and Exons Promoter Binds the Polymerase TATA box Proximal Control Element Facilitates binding of the Polymerase Enhancers Distal Control Element Binds the Activator Proteins RNA Polymerase Unzips the DNA Transcribes the Gene Activators Bind to the Enhancer region Are specific to certain enhancer sequences General Transcription Factors Proteins which aid the binding of Polymerase Are not Gene-Specific

16 Initiation of Transcription
To begin transcription the promoter region must bind not only the RNA polymerase, but also a complex of transcription factors, coactivators, mediator proteins and activators Most of these assemble at the promoter or the proximal control elements Activators , however, bind to the Distal elements (Enhancers) Transcription begins when these fold back and contact the rest of the Initiation complex at the promoter ature=related

17 Enhancers Each gene has its own combination of enhancers
Each enhancer binds a specific Activator protein Genes that are associated with the same set of enhancers will initiate transcription with the same Activators As a result, some genes will be transcribed under the same conditions of control, which makes sense especially if those genes are for enzymes in the same metabolic pathways It also means that a particular set of activator proteins will result in a characteristic cellular structure and behavior, which has great significance for embryonic development

18 Differentiation Compare the enhancer region of the Albumin gene with the enhancer region of the Crystallin gene Which enhancer do they have in common? Which enhancers differ? One combination of Activator proteins will initiate transcription of the Albumin gene but not the Crystallin gene (and vice versa)

19 Differentiation So if two different cells in an early embryo are exposed to a different set of Activators they will produce proteins characteristic of certain cell types Those cells will differentiate. They will become more different in their structure and activity They will

20 Zygote to Tadpole This video is a time lapse video that condenses 3 weeks of real time into 6 minutes of video It shows the embryonic development of the Alpine Newt Blastula stage at :36 Gastrulation at 1:00 Neural Fold at 1:44 Limb buds at 2:24 Distinct form at 3:11 Heartbeat at 3:42 “Becoming: From Zygote to Tadpole, in six stunning minutes” ch?time_continue=374&v=7Q9 VyHJ1l2Q

21 Steroid Hormones Many activators are actually a complex of a steroid hormone bound to a receptor protein The steroid enters the cytoplasm and binds to the receptor The complex forms an activator, which in turn promotes transcription of specific genes The cell makes specific proteins as a response to the presence of the hormone

22 Post-Transcriptional Controls
Eukaryotic cells process RNA in a variety of ways after transcription but before the RNA leaves the nucleus 5’ Cap and Poly A tail Slow down degradation of the mRNA, resulting in more protein being translated from a single transcript Differential Splicing of Introns and Exons Allow for a variety of different proteins to be produced from a single gene

23 Differential Splicing
Introns = Intervening Exons = Expressed A cell can make a variety of different polypeptides from the same transcript by splicing out different introns and keeping different exons

24 Translational Controls
Translation occurs in the cytoplasm. It requires amino acids, tRNA’s and Ribosomes Regulatory proteins can affect translation by either aiding or preventing the binding of the ribosome to the UTR (untranslated region) upstream of the start codon

25 Translational Controls
The transcript can be translated multiple times before it finally degrades The 5’ cap and Poly A tail increase the longevity of the mRNA transcript Cells may also degrade the mRNA to limit the amount of protein produced from the transcript

26 MicroRNA and Small Interfering RNA
Both micro RNA (miRNA) and small interfering RNA (siRNA) begin as short sequences of double stranded RNA. They are formed differently, but behave in a similar way Both will first bind to a protein, and then to the mRNA. At this point they will either block the ribosome or degrade (break down) the mRNA Both actions will limit the production of protein

27 Proteasomes and Protein Degradation
Gene expression is the result of protein production The controls discussed so far have address controls that affected the production of proteins Once a protein has been produced, it may remain in the cell for long periods or degraded Proteasomes are structures that break down proteins that have been tagged for destruction (by the attachment of “ubiquitin”)