Unit 3 Regulation of Gene Expression

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1

Gene Expression

translation of info encoded in a gene into a protein or RNA

2

Advantages of Gene Regulation

*Cellular control of structure & fx, *versatility and adaptation, *conservation of energy, *development- stages of protein synthesis

3

Regulated Transcription in Prokaryotes

Mostly regulated on the level of *initiation; one promoter for all genes in an operon

4

Repressors

prevent binding of RNA pol to promoter. *Constitutively active, *Corepressor required to activate repressor (incr. [Trp] inhibits transcription of Trp operon. Trp is corepressor of Trp operon)

5

Inducers

stimulate transcription, usually nutrients or their metabolites, bind represser and release it from operator. No inducer = no expression.

6

Lac Operon

encodes for lactose metabolism; allolactose (lactose metabolite) is an inducer. Glucose prevents activation of lac operon. Enzymes for Glucose met constantly produced.

7

cAMP-CRP Lac Operon Cont.

necessary coactivator (low transcription w/o). Low Glucose leads to incr. [cAMP], cAMP binds CRP and binds to operon and stim. pol binding and transcription

8

Attenuation of Transcription

Trp operon: [Trp] is high, ribosome rapidly translates generating a hairpin loop between sequences 3 & 4 = termination. [Trp] is low, ribosome stall at Trp codons and hairpin does not form & entire operon is transcribed.

9

Regulation of Gene Expression in Eukaryotes

Chromatin structure: chromatin remodeling and gene rearrangement, Transcription: TFs affect binding of RNA pol, Maturation of mRNA- processing incl. alternative splicing, Translation: initiation and mRNA stability

10

What happens if a promoter region is a part of nucleosome?

Transcription does not occur- requires chromatin remodeling

11

Genetic Imprinting

some genes are only actively transcribed on paternally or maternally inherited chromosomes.

Gene expression is also affected by rearrangements, amplification, and deletion

12

Epigenetic Changes in Chromatin

DNA methylation and other histone modifications alter structure of chromatin and gene expression- tissue and cell specific

13

Angelman Syndrome

intellectual and developmental delay; inability to express gene UBE3A on paternally inherited *chromosome 15 by imprinting; mutation (15%) deletion (70%) of maternal gene- paternal imprinted gene cannot be expressed. Affects 1:12K-20K

14

Prader-Willi Syndrome (PWS)

Loss of genes active only on paternal *chromosome 15 (opposite angelman syndrome); genes for small nucleolar RNAs (snoRNAs); low muscle tone & instable appetite in childhood- hyperphagia & obesity; 70% deletion of region of paternal chromosome 15- maternal uniparental disomy (UPD)

15

Prader-Willi Syndrome (PWS) Cont.

25% caused by two copies of maternal chromosome 15. Affects 1:10K-30K

16

Silver-Russell Syndrome

dwarfism caused by imprinting error; loss of methylation of H19 & IGF2 genes on *chromosome 11 leads to slow growth, *can receive 2 maternal chromosome 7- no expression of genes only in paternal copy. Incidence 1:3K-100K

17

DNA Methylation and Cancer

DNA *hypermethylation can *silence tumor suppressors (DNA repair, neg regulators of cell cycle, neg regulators of DNA repl, & chromosomal stability) and *hypomethylation activate proto-oncogenes (cMYC & H-RAS)

18

Methylation of DNA

Cytosine can be methylated by *DNA methyltransferases (~1% of bases are methylated); genes are less actively transcribed (globin genes methylated in cells where not expressed); regulated gene expression during differentiation. *Overall hypomethylation in cancer cells

19

ATP-dependent Chromatin Remodeling Complexes

Unwind DNA from Nucleosome

20

Covalent modification of Histones

Histone Acetyltransferases (HAT) create active chromatin.

Histone deacetylases (HDAC) create repressed chromatin

*Lys residues in tail of histone are affected

21

Basal Transcription Complex

TBP and general TFs complexed with RNA pol II

22

Gene Control Regions

TFs can bind and increase transcription 1K-fold; located upstream and downstream of promoter

23

Gene Specific Transcription Factors

Activators, Inducers, Repressors, Nuclear Receptors; *have a DNA binding domain, domain for mediator proteins (bind coactivators, corepressors, or TBP-associated factors that can be gene-specific or general); steroid hormone bind corepressor or coactivators; some TFs can induce or inhib.

24

Lipophilic Hormones

Regulate transcription through nuclear receptors (NRs)- gene specific TFs

25

Hormone Response Elements (HRE)

Nuclear receptors (NRs) that bind regulatory sequence and induce or repress transcription

26

Nuclear Receptors (NRs) Domains

Several Domains: ligand binding domain, DNA binding domain, dimerization domain; transactivation domain binds coactivator proteins; nuclear localization signal

27

Glucocorticoid Receptors

bind cortisol @ cytosol (Steroid-Thyroid Hrmn Recptr), recptr dissociates from heat shock protein, expose nuclear localization signal (NLS), form dimer, translocate to nucleus, bind glucocorticoid response element (GRE), transactivation domain bind mediator proteins and activate transcription.

28

Thyroid & Retinoid X Receptors

(Steroid-Thyroid Hormone Receptor); bound to DNA constitutively, Thyroid & Retinoid form heterodimer; absence of thyroid hormone dimer binds corepressor and inhibits transcription. Thyroid hormone causes binding of coactivator and activation. No hrmn receptor = disease

29

Androgen Insensitivity Syndrome (AIS)

patients produce androgens but lack receptor; complete (ACIS)- woman with nearly normal female body despite XY karyotype; ACIS affects 2-5:100K; Incomplete can include other disorders: *Gynecomastia (breast development in men), *Cryptorchidism (1 or both testes fail to descend after birth)

30

TFs Activation (Regulation)

availability of coactivators and mediators are critical for TF activation;

31

TFs Activity Modulation (Regulation)

activity can be modulated by changes in [TF], binding of inhibitor or stimulator, stim. of nuclear entry, phosphorylation (CREB by PKA or MAP kinase)

32

Alternative Splicing of mRNA

some genes can be spliced in two or more alternative ways (~80% of genes), produces diverse set of proteins, alternative types of splicing ie exon skipping

33

ApoB mRNA

alternative splicing results in apoB48, which increases fat absorption in the intestines, or apoB100, which is associated with more atherogenic lipoproteins. Low or no hepatic apoB mRNA leads to incr. levels of VLDL & LDL

34

Degradation of Eukaryotic mRNA

progressive shortening of poly(A) tail; loss of tail leads to rapid degradation (mRNA turnover) by *cytoplasmic exosome @ 3', or in *P body (yeast) or *cytoplasmic foci (humans) at 5' end decapped mRNA

35

Ferritin

main iron storage protein in cel; synth when iron is high; iron respone element (IRE) near 5' end of mRNA. Low iron- IRE-BP prevents translation. High iron- IRE-BP binds iron, dissociation from IRE, translation of ferritin mRNA

36

Transferrin

Iron transporter in blood. Low iron- more receptor & vice versa through same function of ferritin except mRNA is degraded w/ high iron for less receptor.

37

Prokaryote vs Eukaryote Regulation of Gene Expression: Prokaryote

Prokaryotes: inductinon and repression of transcription by repressors, inducers, corepressors, and coactivators

38

Prokaryote vs Eukaryote Regulation of Gene Expression: Eukaryote

Eukaryotes: chromatin modification and remodeling- HATs & HDACs, DNA & histone methyltransferases & demethylases, regulation of transcription initiation- + & - TFs, translation- mRNA editing, mRNA degradation, binding of ribosome to mRNA