Expression of Human Genes

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Chapter 8 Expression of Human Genes Regulation of
gene expression occurs at three levels A. At
the transcriptional level B. Post-transcriptional
C. Epigenetic and long range control
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• A. Control of gene expression by binding of
  trans-acting protein factors to cis-acting
  regulatory sequences in DNA and RNA
• Control by DNA-binding proteins
• Control by RNA-binding proteins

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• 1. Ubiquitous transcription factors are required
  for transcription by RNA polymerase I and III
• Requirements for transcription by RNA
  polymerase I (18S, 5.8S and 28S RNA)
• Requirements for transcription by RNA
  polymerase III (tRNA and 5S RNA)

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• 2. Transcription of polypetide-coding genes
  require a set of cis-acting elements and tissue-
  and developmental-specific transcription factors
• RNA polymerase II is responsible for
  transcribing protein-coding genes and certain
  snRNA genes.

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• 3. Transcription factors contain conserved
  structural motifs that permit DNA binding
• Transcription factors for humans have two
  distinct functions
• An activation domain
• A DNA-binding domain

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Four types of transcription factors 1. The
leucine zipper motif 2. The helix-loop-helix
motif 3. The helix-turn-helix motif 4. The zinc
finger motif
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4. Several mechanisms permit transcriptional
regulation of gene expression in reponse to
external stimuli (a) Ligand-inducible
transcription factors (for small hydrophobic
hormones such as steroid which diffuse through
plasma membrane) Transcription factors (often
known as hormone nuclear receptors) are activated
by binding to a ligand then bind to a response
element located in the promoter regions of about
50-100 target genes and activates their
transcription. The hormone nuclear receptors are
characterized by two conserved domains - a DNA
binding domain (68 amino acid long). It contains
zinc fingers and binds to DNA as a dimer. - a
ligand binding domain (240 amino acid)
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(b) Activation of transcription factors by
signal transduction For hydrophilic signaling
molecules that cannot diffuse through plasma
membrane. Instead they bind to a specific
receptor. Two genral mechanisms permit
transmission of signals from cell-surface
receptors to the nucleus -i- Protein kinases
are activated then translocated from the
cytoplasm to the nucleus where they phosphorylate
target transcription factors. E.g. hormonal
signaling through cyclic AMP pathway -ii-
Inactive transcription factors stored in the
cytoplasm are activated by phosphorylation and
translocated into the nucleus. E.g. activation of
NF-kB via protein kinase C signaling
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5. Translational control of gene expression can
involve specific recognition by RNA-binding
proteins of regulatory sequences within the
untranslated sequences of RNA Several cis-acting
regulatory elements, mostly are bound by
trans-acting RNA-binding proteins and regulate at
the translational level in three ways -i-
intracellular RNA localization -ii-
translational control of gene expression in
response to external stimuli. E.g. The
IRE-binding protein regulates the production of
ferritin heavy chain and transferrin receptor by
binding to iron-response elements (IREs) in the
5- or 3-untranslated regions. -iii-
translational control of gene expression of gene
expression during early development. Upon
fertilization no new mRNA is transcribed until
the 4-8 cell stage and regulation occurs at the
translational level for maternal mRNA synthesized
during oogenesis.
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• B. Alternative transcription and processing of
  individual genes
• 1. Transcription of a single human gene can be
  initiated from a variety of alternative promoters
  and can result in a variety of tissue-specific
  isoforms. This results in
• Tissue-specificity e.g. dystrophin gene
• Developmental stage-specificity e.g. the
  insulin-like growth factor II gene
• Differential subcellular localization e.g.
  soluble and mebrane-bound isoforms
• Differential functional capacity e.g. the
  progesterone receptor
• Sex-specific gene regulation the Dnmt1
  methyltransferase gene

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2. Human genes often encode more than one
product as a result of alternative splicing and
alternative polyadenylation events. E.g. -i-
Differential splicing in the WT1 Wilms tumor
gene -ii- Alternative polyadenylation of the
calcitonin gene results in tissue-specific
products
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3. RNA editing is a rare form of
post-transcriptional processing whereby
base-specific changes are enzymatically
introduced at the RNA level. Types of RNA
editing in humans (i) C---gt U, occurs in humans
by a specific cytosine deaminase e.g. The
expression of the human apolipoprotein B gene in
the intestine involves tissue-specific RNA
editing (ii) A ---gt I, the amino group in in
carbon 6 of adenine is replaced by a carbonyl
group. I then acts as a G. Occurs in some
ligand-gated ion channels. (iii) U ---gt C, in
mRNA of the WT1 Wilms tumor gene (iv) U ---gt A,
in alpha-galactosidase mRNA
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