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Regulation of Gene Expression-1

Gene expression is regulated at multiple levels, including pre-transcriptionally through epigenetic mechanisms like DNA methylation and chromatin remodeling. Transcriptional regulation occurs through interactions between cis-acting elements like promoters and enhancers/silencers with trans-acting regulatory proteins. Post-transcriptional regulation includes alternative splicing and microRNAs decreasing mRNA expression. Translational regulation can be controlled by phosphorylation of initiation factors like IF2 during stress. Post-translational modifications further regulate protein function. Overall, tight regulation of expression at DNA, RNA, and protein levels ensures the correct amount and timing of gene products.

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36 views

Regulation of Gene Expression-1

Gene expression is regulated at multiple levels, including pre-transcriptionally through epigenetic mechanisms like DNA methylation and chromatin remodeling. Transcriptional regulation occurs through interactions between cis-acting elements like promoters and enhancers/silencers with trans-acting regulatory proteins. Post-transcriptional regulation includes alternative splicing and microRNAs decreasing mRNA expression. Translational regulation can be controlled by phosphorylation of initiation factors like IF2 during stress. Post-translational modifications further regulate protein function. Overall, tight regulation of expression at DNA, RNA, and protein levels ensures the correct amount and timing of gene products.

Uploaded by

lorenoh21
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128 Regulation of gene expression

Regulation of gene expression


Gene expression: The process by which the information contained within the gene
becomes a functional product (mRNA or protein)
▪ The process needs to be strictly regulated to ensure that the correct amount of
proteins are produced only when body needs them.
▪ Regulation of gene expression means regulation of transcription and translation.
▪ Any disruption to this regulation can lead to serious consequences.
Genes are classified into:
Regulated (Inducible) genes:
▪ Represent the majority of genes.
▪ Expressed only under certain conditions (encode proteins only when they are
required), as globin gene.
▪ As genes which are negatively regulated by a repressor, they are expressed in presence
of an inducer or de-repressor.
Unregulated (constitutive or housekeeping) genes:
▪ Expression of these genes is not regulated (continuously expressed at a fixed rate).
▪ They code for products that are involved in basic cellular functions as β actin gene.
Regulation of gene expression in eukaryotes
▪ Eukaryotes requires wide range of regulations due to:
➢ Complexity of eukaryotic genome
➢ Presence of nuclear membrane
Eukaryotic regulation of gene expression occurs on multiple levels:
I. Pre-transcriptional regulation
II. Transcriptional regulation
III. Post-transcriptional regulation
IV. Translational regulation
V. Post-translational regulation

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129 Regulation of gene expression

I. Pre-transcriptional regulation
1. Epigenetic mechanisms:
▪ Epigenetics means around the gene
▪ Changes in DNA and histones that affect gene
expression without altering sequence of DNA
A. DNA methylation:
▪ Methylation of cytosine to 5 methyl cytosine
▪ occurs by DNA methylase (methyl transferase)
▪ At certain CG sequence
▪ Result in chromosomal inactivation (transcriptional
silencing) → ↓ access to DNA
▪ Occurs during cell differentiation especially in fetal development
▪ Demethylation reverse the process
B. Chromatin remodeling:
▪ The cellular genome is packaged together with histones
into nucleosomes
▪ Initiation of transcription is prevented if the promoter is a part of a nucleosome
▪ Activation of a gene for transcription requires change in the chromatin →↓ of the DNA
supercoiling around The histone to allow access of RNAP and transcription factors.
▪ This occurs through different mechanisms that include:
Histone Acetylation:
▪ Occurs by Histone acetyl transferase (HATs)
▪ HAT transfers acetyl group from acetyl CoA to lysine residue in the tail of histone
octamer
▪ This removes the +ve charge from the ε amino group of lysine → ↓ the +ve charges of
Histone
▪ This ↓ electrostatic interaction between the histone & the –ve charged DNA
▪ This result in unwinding of DNA → ↓ Supercoiling → Activation of transcription → ↑
access to DNA.
▪ Deacetylation can occur by histone deacetylases (HDACs)

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130 Regulation of gene expression

2. Amount of DNA:
Def.: Change in the number of copies of a gene can affect the amount of the Ptn
produced
A. Gene amplification:
Def.: ↑ No. of genes
Example: Amplification of DHFR (Dihydro folate reductase) gene in methotrexate treated
cancer cell

Thymidylate Synthase Kinases


dUMP dTMP dTTP DNA Synthesis

CH2 THF DHF

DHF Reductase Cell division


X
Methotrexate
THF

Q: Some cancer cells are resistant for methotrexate …… why?


B. Gene diminution:
Def.: Removal of gene or genes from the genome
Example: Removal of all genes during development of RBCs
3. Gene rearrangement:
Example: Occurs in immunoglobulin genes → Diversity of the immunoglobulins
▪ Light chains and heavy chains are encoded by several hundred of gene segments.
▪ Re-arrangement and recombination of those gene segment allow generation of several
millions of immunoglobulins
▪ This gives the diversity required for recognition the enormous number of antigens

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131 Regulation of gene expression

II. Transcriptional regulation


▪ Regulation of gene expression at the level of transcription occurs through interaction
between cis and transacting elements:
1. Cis-acting element
▪ These are DNA sequence flanking a gene usually embedded in the non-coding regions
of the genome.
▪ They affect the expression of genes only in same chromosome.
▪ The interaction between these DNA segments and regulatory molecules as
transcription factors can induce or repress transcription.
▪ Cis-acting elements include:
a. Promoter:
▪ 2 types of sequence elements are present
▪ TATA box and CAAT and GC box
b. Enhancers and silencers
Enhancers:
Def.: Elements on DNA ↑ the rate of transcription
Site: Close to or thousand bp away from the promoter, on either strand of DNA
Mechanism: Bind to certain proteins that facilitate binding of transcription factor to the
promoter
Silencer:
Def.: Element on DNA ↓ the rate of transcription
Mechanism: Bind to certain proteins that inhibit transcription.
C. Hormone response elements (HRE):
Def.: Elements on DNA that binds to hormones → regulation of gene expression
Examples: Steroid, thyroid, retinoid and vit. D response elements
3. Trans-acting regulatory proteins:
▪ Regulatory proteins which can diffuse from their site of synthesis to DNA binding site.
▪ For example, trans acting molecule is transcribed from chromosome 11 and regulate a
gene on chromosome 6
III. Post-transcriptional regulation
1. Capping, poly A tailing and splicing: discussed in transcription
2. Micro RNA (miRNA):
▪ miRNA are small non coding RNA molecules (22 nucleotides)
▪ miRNA is synthesized by RNAPII
▪ They reduce expression of target mRNA by producing its degradation or blocking its
translation

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132 Regulation of gene expression

IV. Translational regulation


▪ Translation can be regulated by IF2 and IF4
1. IF2:
▪ One of the control points for protein synthesis
▪ Phosphorylated by protein kinase
▪ Phosphorylation occurs during stress & starvation (no energy is available for initiation)
▪ When phosphorylated IF2 becomes inactive → Inhibition of initiation of translation
2. IF4 (cap binding proteins) and Poly A tail binding protein:
▪ IF4 binding proteins interact with poly A tail binding proteins to help to direct the 40S
ribosomal subunit to the 5` end of the mRNA
V. Post-translational modification of proteins
See before

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