REGULATION OF GENE
EXPRESSION
DR.LAKSHMIPRIYA.M
SPECIFIC LEARNING
OBJECTIVES
◦1. What is gene regulation ?
◦2. Prokaryotic gene regulation
◦3. Eukaryotic gene regulation
CENTRAL DOGMA & GENE EXPRESSION
GENE EXPRESSION AND
REGULATION
◦ THE GENE IN DNA CODES FOR RNA AND PROTEIN. FORMATION OF THESE
PRODUCTS FROM A GENE IS CALLED GENE EXPRESSION
◦ ONLY A FRACTION OF GENES IS EXPRESSED THE REST ARE REPRESSED
◦ THE PROCESS OF TURNING GENE OFF AND ON IS KNOWN AS GENE
REGULATION.
PRINCIPLES OF GENE
REGULATION
HOUSE
REPRESSIO
KEEPING INDUCTION
N
GENES
REGULATO
RY SIGNAL
House keeping genes-
Constitutive genes
House keeping genes-Constitutive genes:
Some genes are expressed almost always in all cells.
e.g: genes for Enzymes of Glycolysis
INDUCTION AND
REPRESSION
◦ Induction is the phenomenon of increased synthesis of protein or
enzyme in response to certain signal.
◦ Such enzymes are said to be inducible; and the signals are called
inducers.
◦ Induction is turning "on" the switch of the gene.
◦ Repression is turning "off" the gene expression.
DIFFERENT TYPES OF CELLULAR RESPONSE TO
REGULATORY SIGNAL
X AXIS – GENE EXPRESSION
Y AXIS- TIME
TYPE C (SUSTAINED
RESPONSE)The
response is initially
low, but once the
signal is introduced, it
increases and remains
high, even if the signa
stops.
Eg: immune response
TYPE B (TRANSIENT
TYPE A RESPONSE)The
ON AND OFF RESPONSE response peaks
The response follows sharply after the
the signal input almost signal is introduced
exactly, turning on and but then quickly
off as the signal declines, even if the
appears and signal persists.
disappears. Eg: Eg:feed back
REGULATION OF GENE
EXPRESSION
PROKARYOTIC
EUKARYOTIC
OPERON CONCEPT
Francois Jacob & JacquesMonod —1961
Based on lactose metabolism in E.coli..
Lactose metabolism is regulated by induction & derepression of genes of
enzymes of metabolism of lactose
◦ Operon is a unit of gene expression.
Contains Structural gene,
Regulator genes ,
Operator genes,
Promoter elements &
Control elements .
OPERON CONCEPT
◦ Bacterial cell: LAC OPERON
STRUCTURAL
REGULATORY
Reg
Lac Z –Promo
u
Z
Beta galactosidase
OPER Y A
Lac Z - Galactoside
Lac Y - Permease
Lac A - Thio galactoside Transacetylase
LAC OPERON(E. Coli)
E. COLI
TRYPTOPHAN
(TRP)
OPERON
EUKARYOTIC REGULATION OF
GENE EXPRESSION
POST
TRANSCRIPTIO
EPIGENETIC TRANSCRIPTIO
NAL
NAL
TRANSLATIONA
L
EPIGENETIC REGULATION
◦1. HISTONE ACETYLATION
◦2. DNA METHYLATION
◦3. DNA BINDING PROTEINS
HETEROCHROMATIN & EUCHROMATIN
• Heterochromatin -transcriptionally
inactive.
• Methylation of DNA and histones
causes nucleosome to pack tightly.
• Genes not expressed
• Euchromatin less condensed
• Histone Acetylation causes Loose
packing of nucleosome
• Transcriptionally active
• Genes expressed
TRANSCRIPTIONAL
REGULATION
ENHANCERS GENE GENE
AND AMPLIFICATIO REARRANGEM
SILENCERS N ENT
GENE DNA BINDING
GENE LOSS
SWITCHING MOTIFS
ENHANCERS AND SILENCERS
◦ Enhancers are sequences that enhance gene expression
◦ Silencers are sequences that decrease the gene expression
◦ They are located thousands of basepairs upstream or downstream
from the promoter region.
GENE AMPLIFICATION
◦ Repeated initiation of DNA synthesis leading to Production of additional
copies of genes
GENE AMPLIFICATION
◦ E.g:
◦ 1.DHFR gene:
Methotrexate
Anti Folate drug that decreases
DIHYDROFOLATE REDUCTASE
Used as anticancer drug.
After prolonged treatment .,cells resistant
to METHOTREXATE by gene amplification
GENE REARRANGEMENT
◦ A segment from the DNA moves from one location to another
on the genome.
◦ This forms new combination of genes so that several
proteins are encoded.
◦ E.g: Various portions of Antibody producing genes lie at distant
location of DNA of Germ line cell.
◦ The Heavy chain of Ig consists of
Variable Gene(V)
Diversity Gene(D)
Joining Gene(J)
◦ These genes are scattered thro’ out genome of Immunocyte.
◦ These can be transposed next to one another and joined to yield
complete VH gene.
◦ Major role in the generation of Antibody diversity.
GENE REARRANGEMENT
REARRANGEMENT OF DNA
GENE SWITCHING (Eg: Hb
synthesis)
◦ During intrauterine life embryonic Hb
is the first Hb to be formed-two
“Zeta” and two “Epsilon” chains.
◦ By the sixth month of intrauterine
life, embryonic Hb is replaced by HbF
consisting of “α2 and γ2 chains.
◦ After birth HbF is replaced by adult
type of 97% Hb A1 (2α & 2 β) and
3% HbA2 (2α & 2δ)
◦ Thus the genes for a particular class
of Hb are switched off and for another
class are switched on.
GENE SWITCHING
◦Gene expression is shifted from one gene to another.
◦E.g-1.Immune Response.
Primary Response------Ig Ms are synthesised
Secondary response-- Ig Gs are synthesised
◦2.In embryo, α2ε2 α2γ2(HbF---6 months
Intrauterine life)
α2β2(HbA1-At birth)
GENE LOSS
◦ Rare form of regulation
◦ Completely inactivates genes by removing them from Genome.
◦ E.g-Loss of all genes in RBC precursors - loss of Nucleus during
RBC development
DNA BINDING MOTIFS
POST TRANSCRIPTIONAL
REGULATION
RNA ALTERNATE
EDITING SPLICING
RNA
INTERFERE
NCE
PATHWAY
TISSUE-SPECIFIC ALTERNATIVE SPLICING
PRODUCES DIFFERENT PROTEINS OR
ISOFORMS, FROM A SINGLE GENE
mRNA EDITING
◦ Apo B mRNA transcribed in
hepatocytes and small intestinal epithelium
◦ In intestine cytosine in the CAA codon for
glutamine is enzymatically deaminated to UAA
◦ Sense codon converts into nonsense
or stop codon
◦ Shorter protein apo B-48 formed
RNA INTERFERENCE
RNAi- a mechanism- decreased expression of mRNA. Mediated by short, noncoding RNA
called microRNA
Primary miRNA , to pre-miRNA by an endonuclease (Drosha).
In cytoplasm, endonuclease (Dicer) completes the processing of double-stranded miRNA.
Then attaches with RNA induced silencing complex (RISC).
Then it attaches with target protein and result in repression of translation of the mRNA or its
degradation by an endonuclease (Argonaute/Ago/Slicer) of the RISC.
TRANSLATIONAL
REGULATION
◦TRANSLATION INITIATION FACTORS
◦HAIRPIN LOOP AT 5’ END OF mRNA:
E.g-
Regulation of gene of Ferritin
Fe↑----↑synthesis of Ferritin
Fe ↓----↓synthesis of Ferritin
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