Transcript No Slide Title

Molecular Basis for
Relationship between Genotype and Phenotype
genotype
DNA
DNA sequence
transcription
RNA
translation
protein
function
phenotype
organism
amino acid
sequence
Eukaryotic Gene Regulation - Transcription
Expression of genes can be:
- constitutively on (housekeeping genes ... ~15,000
in humans)
- regulated (temporally or spatially ... up to 2000+
unique proteins in differentiated cell)
Differentiation is a manifestation of genes being
selectively turned off.
Regulation of gene expression involves:
- cis-acting regulatory elements
- trans-acting transcription factors
Transcription Factors
Transcription factors have:
1. DNA binding domain (interact with
promoter-proximal elements or
enhancers/silencers)
2. Transactivation domain (activate or
repress transcription, involved in
protein/protein interaction)
Structural Families of Transcription Factors and Regulatory Proteins:
Helix-Turn-Helix:
Many homeotic genes code for TF's of this
class.
Zinc-Finger:
Many steroid hormone receptor protein TF's
belong to this class.
Leucine Zipper:
Proto-oncogenes such as c-jun and c-fos are
genes that encode TF's of this class.
Helix-Loop-Helix:
Certain proto-oncogenes and genes involved
in differentiation encode TF's of this class.
Structural Families of Transcription Factors and Regulatory Proteins:
Zinc-Finger:
Leucine Zipper:
Helix-Loop-Helix:
Enhanceosomes and Synergistic Effect on Transcription
Enhanceosome: protein
complex of trans-acting
factors bound to
appropriate DNA
sequences.
Proteins interact
synergistically to elevate
transcription rate.
In b-interferon gene transcription, TFs recruit a coactivator (CBP)
which is needed for transcription to occur normally.
Formation of the enhanceosome and activation of RNA polymerase
by coactivator are necessary for efficient transcription.
Transcription of b-interferon gene is activated during viral infection.
Tissue-specific Regulation of Transcription
Regulated transcription depends on:
- specific enhancer for gene(s)
- enhancer-specific activator proteins
- correct interaction between enhancer and activator
Tissue-specific regulation requires that the enhancer-specific
activator is present only in cells of that tissue type.
: expression in an abnormal location
“Master Switch” Gene
Eye formation requires over 2000 genes.
eyeless (ey) mutation causes small rudimentary
eyes to form in Drosophila melanogaster.
Small eyes (Sey, Pax-6) in mouse causes similar
phenotype.
Aniridia gene in human (lack of normal iris) shows
considerable homology to ey gene.
Comparison of ey+ and ey Phenotypes
Wild-type eyes
eyeless (ey) eyes
size of ey eyes
“Master Switch” Gene
Wild-type eyeless (ey) gene can be induced
to be expressed ectopically.
eyeless (ey) gene codes for a helix-turn-helix
transcription protein.