1. TOPICS & REFERENCES
• Regulation of Gene Expression
• Regulation of Gene Expression in prokaryotes.
• Structural genes.
• The Operon Model.
• Regulation of Gene Expression in Eukaryotes.
• Histone Modifications and Nucleosomal Chromatin
Remodeling.
• DNA Methylation.
• Promoter Elements.
• Mechanisms of Transcription activation and repression.
• Alternative splicing of mRNA.
• Alternative splicing and Human Diseases - Myotonic
dystrophy (DM).
4. Transcription factors and transcriptional regulation
• Transcription factors are proteins that bind to gene promoters and
regulate_transcription. About 3000 transcription factors regulate the 20,000
genes or so encoded in the human genome.
• Transcription factors contain a set of independent protein modules or
domains, each having a specific role important for the function of
transcription factors.
• They include DNA-binding domains, transcriptional activation domains,
dimerization domains, and ligand-Binding domains.
• Four common types 0f DNA-binding domains are
1. Helix-turn-helix motif,
2. Leucine zipper motif,
3. Helix-Loop-helix motif
4. Zinc finger motif.
• These domains are characteristic proten conformationts that enable a
transcription factor to bind DNA. It is the conformation of these protein
domains that facilitates binding to DNA.
8. Alternative splicing and Human Diseases -
Myotonic dystrophy (DM).
• Since alternative splicing is an important mechanism for the regulation of gene expression, it is not surprising that defects in
alternative splicing are associated with human diseases. Genetic disorders caused by mutations that disrupt RNA splicing are
known as spliceopathies.
• Myotonic dystrophy (DM) is an autosomal dominant disorder that afflicts 1 in 8000 individuals. DM patients exhibit myotonia
(inability to relax muscles), muscle wasting, insulin resistance, cataracts, intellectual disability, and cardiac muscle problems.
Studies have shown that several of these symptoms are caused by widespread alternative splicing defects in muscle cells and
neurons.
• There are two forms of DM (DM1 and DM2), which are caused by mutations in different genes, but with similar outcomes that
lead to splicing defects. DM1 is caused by expansion of a CTG repeat in the 3′ UTR of the DMPK gene. Unaffected individuals
have 5–35 copies of the CTG repeat, whereas DM1 patients have 150–2000 copies. The severity of the symptoms is directly
related to the number of repeats. DM2 is caused by an expansion of a CCTG repeat sequence within the first intron of the
CNBP gene (also known as ZNF9). Unaffected individuals have 11–26 repeats, while DM2 patients have over 11,000 copies of
this repeat; the severity of symptoms is not related to the number of repeats.
• Interestingly, DM is not caused by defects in the proteins encoded by DMPK and CNBP. Rather, repeat-containing RNAs
accumulate in the nucleus, instead of being exported to the cytoplasm, and are bound by proteins that regulate alternative
splicing. In this way, these RNAs sequester splicing regulators and prevent them from regulating many RNAs that encode
proteins important for muscle and neuron function. Strategies to degrade the repeat-containing RNAs, or to block the binding of
the splicing regulators to the RNAs, are currently being researched for therapeutic purposes.
