Control of Gene Expression

Transcription

1 Control of Gene Expression (Learning Objectives) Explain the role of gene expression is differentiation of function of cells which leads to the emergence of different tissues, organs, and organ systems despite the fact that all cells have the same DNA. Recognize the difference between house-keeping genes and cell-specific genes, using the example of the pancreas and its cells Explain the role of gene duplications and transposition in generating families of genes that carry similar but not identical function, using the example of hemoglobin. Define the term pseudogene. Explain the advantage to humans to having members of the globin gene family differentially gene expression during the embryonic, fetal, and adult stages. Learn the five primary levels of control of gene expression by name, sub-cellular location, and mechanism: Chromatin re-modeling or packing, transcription factors, alternative splicing, micro-rnas and RNA interference, and the post translational controls. Recognize the mechanisms and modifications that maximize the number of proteins that can be generated from a more limited number of human genes. 1

2 Control of Gene Expression (Outline) Same DNA different cells House-keeping genes and cell-specific genes From a stem cell to progenitor cells and their daughters. Example: Pancreatic cells Duplications and transposition- gene families advantageous to organisms Example: Globin genes (embryonic, fetal, and adult) 5 primary levels of control o Nuclear: chromatin remodeling (epigenetic factors), transcription, and post transcription o Cytoplasmic: mrna and protein synthesis, post-translational Maximizing number of proteins produced from a fixed number of genes 2

3 Important facts Individuals vary in absolute level of gene expression Gene expression changes over the life time of individuals Environmental factors can impact gene expression by modifying the chromatin structure 3

4 Gene Expression Through Time and Tissue Changes in gene expression may occur over time and in different cell types This may occur at the molecular, tissue, or organ/gland level 4

5 5 Figure

6 Gene Expression Cells express 3-5% of their genes House-keeping genes- all the time Genes turned on or off- internal and external signals Genes turned on only in some cell types not others while others are permanently shut down (Highly specialized nerves or muscle) 6

7 Pancreas The pancreas is a dual gland - Exocrine part releases digestive enzymes into ducts - Endocrine part secretes polypeptide hormones directly into the bloodstream 7

8 Figure 11.3 Figure

9 Ancient Genomic Structural Events - Transposition: a genomic event certain sequences jump about the genome Transposon is a single jumping sequence - Repeated DNA sequences and multiple copies of certain genes. (example; globin genes) 9

10 Hemoglobin Each globin surrounds an iron-containing heme group Figure

11 Hemoglobin Adult hemoglobin has four globular polypeptide chains - Two alpha (α) chains = 141 amino acids - chromosome 16 - Two beta (β) chains = 146 amino acids - chromosome 11 11

12 Organization of Globin Genes in the human genome ᵋ 12

13 Pseudogenes have accumulated too many mutations and produce no functional proteins They are transcribed but are not translated 13

14 Members of both the α and β families are expressed during the developmental stages: embryonic, fetal and/or adult The embryonic and fetal hemoglobins have higher affinity for oxygen than do adult forms, ensuring transfer of oxygen from mother to developing fetus. 14

15 Globin Chain Switching Subunits change in response to oxygen levels Subunit makeup varies over lifetime - Embryo = Two epsilon (ε) + two zeta (ζ) - Fetus = Two gamma (γ) + two alpha (α) - Adult = Two beta (β) + two alpha (α) - The adult type is about 99% of hemoglobins by four years of age 15

16 Globin Chain Switching Figure

17 Control of Gene expression 5 primary levels Nuclear levels Chromatin packing Transcriptional level Post-transcriptional level Cytoplasmic levels Translational level Post-translational level Figure

18 Control of Gene Expression Nuclear level controls 1) Chromatin remodeling = On/off switch 2) Transcription Factors 3) Alternative splicing 18

19 Chromatin Remodeling Nucleosomal beads of chromatin: DNA and histones Beads on a string Chromatin packing is the degree of nucleosome coiling Histones play major role in gene expression Expose DNA when it is to be transcribed shield it when it is to be silenced 19

20 Chromatin Remodeling Specific Chemical modifications that bind to histones and DNA are: - Acetyl group- histones - Methyl groups- histones and DNA - Phosphate groups- histones 20

21 Histone tails DNA double helix Amino acids available for chemical modification Histone tails protrude outward from a nucleosome Unacetylated histones Acetylated histones Acetylation of histone tails promotes loose chromatin structure that permits transcription 21

22 Epigenetic changes Changes to the chemical groups that associate with DNA that are transmitted to daughter cells after cell division 22

23 Disorders of Chromatin Remodeling 23

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25 Maximizing Genetic Information Alternate splicing help to greatly expand the gene number Figure

26 MicroRNAs : class of noncoding RNAs bases long MicroRNAs The human genome has about 1,000 distinct micrornas regulate expression of at least 1/3 rd of the proteinencoding genes Interfere with gene expression by binding to a specific mrna - Degradation - Blocking translation 26

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28 RNA interference (RNAi) Technology for selective silencing of gene expression Protein complex Degradation of mrna Dicer OR mirna Target mrna Hydrogen bond Blockage of translation28

29 Maximizing Genetic Information Figure 11.8 Figure

30 Maximizing Genetic Information Post-translational modifications - Protein cleavage to get two products - Addition of sugars and lipids to create glycoproteins and lipoproteins 30

31 Post-translational modifications To produce functional proteins - enzymatic cleavage - chemical modifications - transport to the appropriate destination Improperly modified proteins are promptly degraded 31

32 Maximizing Genetic Information Dentinogenesis imperfecta - Caused by a deficiency in the two proteins DPP and DSP - Both are cut from the same DSPP protein 32

33 Maximizing Genetic Information Figure 11.8 Figure