Gene expression DNA RNA Protein

DNA

DNA

RNA

Protein

Replication

Transcription

Translation

Degradation

Degradation

InitiationElongationProcessingExport

InitiationElongationProcessingTargeting

Chapter 7: Gene control

Control of gene expression is critical in mediating cellular changes:

•Executing developmental programs•Controlling cell cycle•Responsiveness to regulators

There are many examples of evolutionary variation in promoters and transcriptional regulators

Since all cells in an organism have the same DNA, how do the cells become different?

(1) Some genes are expressed only in specific tissues (e.g., hemoglobin)

Since all cells in an organism have the same DNA, how do the cells become different?

(2) Genes expressed in all cells are termed housekeeping genes:• cytoskeleton building blocks• metabolism• histones, polymerases

Since all cells in an organism have the same DNA, how do the cells become different?

(3) Even housekeeping genes are expressed at different levels-metabolic profiles of red and white muscle

Since all cells in an organism have the same DNA, how do the cells become different?

(4) Post-transcriptional processes (Fig 7-5) also critical in regulating function:-mRNA processing-mRNA transport and localization-mRNA degradation-translation-post-translational modification-3-dimensional organization-compartmentation-protein degradation

Fig 7-5. Gene expression is controlled at many levels

Cells can change expression in response to external signals

Many cells use hormonal signals to trigger changes in gene expression:

e.g., glucocorticoids induce changes in metabolic enzyme expression in liver

Cells can change expression in response to external signals

Different cells respond differently to the same hormones:

e.g., glucocorticoids in liver: induction of genes that enhance conversion of amino acids to glucose.

-in adipocytes, glucocorticoids repress the same gene

Transcriptional control

Genes are regulated by promoters (regions upstream of coding region)

Genes can also be regulated at sites that are distant from promoters (even in introns)

Gene regulatory proteins

Regulatory regions of DNA have short sequences (elements) that bind specific gene regulatory proteins

e.g., Sp1 binds GGGCGGCCCGCC

These proteins recognize subtle differences in the structure of the outside of the major groove of the DNA double helix

Gene regulatory proteins

Each protein differs in how it binds DNA and how it interacts with other proteins

Several common DNA binding motifs including:

-helix-turn-helix motif (Fig 7-14), include homeodomain proteins

-zinc finger proteins (Figs 7-17-19)

-leucine zippers (Fig. 7-21)

-helix-loop-helix (HLH) (Fig 7-25)

Gene regulatory proteins

DNA binding ability of gene regulatory proteins can be influenced by:

-localization

-dimerization (homodimers vs heterodimers)

Tryptophan repressor is a simple model of ligand-dependent gene regulation

(Fig-7-34, 7-35)

Repressor protein can bind DNA and trp

If trp absent, repressor cannot bind DNA (un-repressed)

When trp available, repressor binds and prevents RNA Pol from binding gene

Eukaryotic gene expressionWhat regulates transcription (Fig 7-41)

Promoter: binding site for RNA Pol II and general transcription factors

Other regulatory sequences can be far away (even 50,000 bp)

Activators (or enhancers) bind to specific DNA sequences (modify local DNA structure)

Eukaryotic gene expression

Gene activators

Activators can work synergistically (Fig 7-47)

Order of binding of activators and combination of activators influences transcription (Fig 7-48)

Gene repressors

Repressors can work many different ways (Fig 7-49)

-competition with activators for sites

-masking activation site on activator

-disruption of general transcription factors

-affecting chromatin remodelling

Co-activators and co-repressors

These proteins do not bind DNA but bind DNA-binding proteins (Fig 7-50)

Myogenesis: an example of programmed transcriptional regulation (Fig 7-72)

Precursor cells are myoblasts

Hormonal conditions cause differentiation: turning on suites of muscle-specific genes in the appropriate order

Hormones induce expression of myogenic factors (transcription factors)

Control of gene expression1. Localization of transcription factors

Xkinase

kinase

Hormone

Control of gene expression2. Dimerization

kinase

kinase

Hormone

Control of gene expression3. Affinity for DNA (phosphorylation dependent)

kinase

kinase

Hormone

Control of gene expression4. Affinity for DNA (ligand dependent)

Hormone

Control of gene expression5. Affinity for DNA (ligand dependent)

Hormone