Regulation of Gene Expression Flashcards
A gene is defined as a…
segment of DNA that is
transcribed into RNA and its associated
transcriptional control regions
All letters in a gene name is
italicized
Human gene names are designated with (2)
all
capitalized and italicized letters
Mouse gene names are designated with the
first letter capitalized and all letters italicized
General Requirements: (1)
Transcriptional machinery
Gene Specific Requirements (4)
Intracellular hormone-receptor complexes
Intracellular second messengers
Gene specific (class specific) transcription factors
Gene regulatory sequences
Intracellular second messengers
Peptide hormones that bind to cell membrane receptors
Intracellular hormone-receptor complexes
Steroids (estrogen, testosterone, Vit D3, etc.) and their cognate receptors
Proteins Involved in Regulating Gene
Expression (7)
• Activators / coactivators • Repressors / corepressors • Mediators and DNA binding proteins • Chromatin remodeling proteins • Histone acetylase / deacteylase • Histone methylation • DNA methylation (selective CpG dinucleotides to produce 5-meC)
Helix-loop-helix
common in transcription factors and consists of α helices bound by a looping stretch of amino acids
DNA binding Zinc Finger Motifs
multiple types, but all have a bound zinc metal ion(s) associated with the protein. Some have an α-helix plus β-sheet structure, others have a more helix-turn-helix structural motif. Can be monomers or dimers
Helix-turn-helix
DNA binding motif consisting of two α helices joined by a short stretch of amino acids
Leucine Zipper
Two proteins each with an α-helix (formed largely by consecutive leucine residues) form a Y-shaped coiled-coil structure. Results in both protein and DNA binding
The majority of DNA binding proteins function as (2)
dimers or tandem clusters
The leucine zipper is capable of
promoting both DNA binding
and dimerization
In prokaryotes, the repressor and activator binding sites
are generally closely juxtaposed to the
RNA Polymerase
binding site
In eukaryotes the experimental evidence has shown that
DNA regulatory sequences can be
located at great
distances relative to the start site of transcription, be
found in the 5’- or 3’-flanking regions, and in introns
TATA Box
located ~25-30 bp 5’ of the start site of
transcription, binds TBP subunit of TFIID
INR
Contains start site of transcription for many RNA Pol II
genes, binds TFIID
DPE
located at +30 (3’) of the start site, binds TFIID
BRE
located at -35 (5’) of the start site, binds TFIIB
DNA is not a
rigid linear structure
Many approaches available today from (2)
GWAS to linkage analysis to DNA sequencing
Linkage Analysis (old school approach) (2)
– The autosomes and X-chromosome are amenable to linkage mapping studies because they undergo recombination.
– The Y-chromosome with the exception of the psuedoautosomal region does not undergo recombination
The most commonly use current technology is the rapid DNA/RNA sequencing coupled with software and databases to identify
mutations in genes
Exome sequencing allows us to identify
causal mutations in those cases where a large family suitable for linkage analysis is not available
DNA Sequencing (4)
• Genome sequencing • Exons (Exomic sequencing) • mRNA (Transcriptomic sequencing or RNA- seq) • Epigenomics
Epigenomics (3)
– DNA methylation
– ChIP sequencing
– Ribosome profiling
rare bone diseases (3)
osteoporosis pseudoglioma sindrome (OPPG)
high bone mass (HBM)
sclerosteosis/van buchem disease
Human mutations in LRP5 give rise to (2)
low or high bone
mass
Loss-of-function Mutations:
Osteoporosis
Pseudoglioma Syndrome
Gain-of-function Mutations:
High Bone Mass and
other increased bone mass phenotypes
Sclerosteosis & Van Buchem’s Disease are
caused by Mutations in the
SOST Gene
sclerostin Binds LRP5/6 and Inhibits
Wnt/β-catenin Signaling
Sclerostin is Expressed in
Osteocytes
Romosozumab (EVENITY) is used for treatment of
post menopausal osteoporosis in when at a high risk for fracture
potential risks of Romosozumab (3)
myocardial infarction, stroke and cardiovascular death
