Regulation of gene expression in a multicellular organism occurs at
several levels. Most of this regulation occurs at the level of
transcription.
Regulation of Transcription
The first step in regulating gene expression is regulation of
transcription. This is done at four levels in a cell.
- Chromatin Structure (condensed or relaxed)
- Necessary transcription factors are expressed in that cell
(regulated by other TFs)
- Necessary transcription factors are active in that cell (through
signal transduction)
- Post-transcriptional regulation
1. Chromatin Structure (condensed or relaxed)
In general, if a region of a chromosome is condensed
tightly around histones it is transcriptionally inactive.
Likewise, if a region of a chromosome is in an exposed
loop it can be transcriptionally active.
This process is regulated by acetylation and methylation
of histones.
•Acetylation
of histone usually turns a gene on.
•Methylation
of histone or of DNA usually turns a gene off.
•Phosphorylation
of histone can turn a gene on
or off
Transcription Factors (TFs) can bind to these exposed
loops and stimulate transcription. This can occur over fairly large
distances (1000s of bp). For more on the action of TF on exposed
loops of DNA see the article on Role
of DNA and chromatin structure.
2. Necessary transcription factors are expressed in that cell
(regulated by other TFs)
Transcription Factors are proteins, and like other proteins, need to
be transcribed and translated from genes. This requires the
presence of the appropriate transcription factors in the cell.
See the article on Hepatocyte
nuclear factors (HNFs) for more on cascades of TFs regulating the
expression of other TFs..
3. Necessary transcription factors are active in that cell
(through signal transduction)
In addition to the appropriate transcription factors being
present in a cell, they must be in an activated state. This is
usually done through some external signal to the cell triggering a cascade
within the cell. The 1986 Nobel
Prize in Medicine was awarded for research on Growth Factors and the
signals they send to cells.
This can occur through three mechanisms.
-
Binding to a ligand (steroid
hormone receptors/transcription factors)
-
Phosphorylation
-
Binding to other proteins
Signal transduction refers to a signal being passed from the outside of
a cell, through a series of proteins and second messengers inside the
cell, and finally resulting in the activation of a transcription
factor. The diagram above shows a typical Kinase cascade.
4. Post-transcriptional regulation of gene
expression
After an RNA is transcribed it is not necessarily
translated. Both proteins and RNAs can interfere with translation
and mRNA stability. The 2006
Nobel Prize in Medicine was awarded for the discovery of these
interfering RNAs.
Proteins can bind to a mRNA and prevent it from being
translated. Exo and endonucleases can also degrade mRNAs.
Special antisense RNAs called microRNA or siRNA (small
interfering RNAs) can bind to complementary regions on a mRNA and target
the mRNA for destruction by specific nucleases, or prevent translation
by forming dsRNA.
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