Regulation of gene expression in eukaryotes

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Regulation of gene expression in eukaryotes
Lodish chapter 7.4 and 7.6
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(No Transcript)
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The Mediator helps to create a nucleosome-free spa
ce for the preinitiation complex
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HAT
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HDAC
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Transcription factors have distinct DNA-binding
and activation domains
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Heterodimer formation allows for a large
number of combinations
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Members of the nuclear receptor superfamily form
homo- or heterodimers
activation domain in presence of ligand

repression domain
in absence of ligand
(in heterodimeric receptors with RXR)
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Lipid soluble hormones do not act
through membrane-bound receptors, but must enter
target cells
(often used to treat pre-cancerous oral lesions)
steroid non-steroids
(thyroid hormone)
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Homodimeric hormone receptors Estrogen receptor
(ER/ER) binds estrogen, important for female
sex determination, blocked by Tamoxifen in breast
cancer patients undergoing chemotherapy Glucocorti
coid receptor (GR/GR) binds cortisol, among
other steroids, and activates gluconeogenesis in
the liver These receptors are usually in the
cytoplasm and are translocated into the nucleus
upon ligand binding.
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Heterodimeric hormone receptors
(dimerization with RXRretinoid X receptor)
Vitamin D3 receptor (RXR/VDR) binds vitamin D3,
important for bone formation and Ca2
metabolism Retinoic acid receptor
(RXR/RAR)retinoic acid is oxidized vitamin A.
Induces differentiation of cycling cells. These
receptors are usually in the nucleus and act as
repressors (through the recruitment of
histone deacetylases HDACS by the ligand
binding domain) in the absence of ligand. Ligand
binding induces a conformational change
that releases HDACs and turns the ligand binding
domain into an activator domain.
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Homodimeric receptors recognize inverted
repeats, heterodimeric receptors bind to direct
repeats in hormone response elements
receptor monomers in inverted orientation recep
tor monomers lie in the same orientation
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Nuclear translocation of hormone receptors
VD
VD
VD
VD
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Mammalian control elements can be located up
to 50 kb away from the transcription start site
hormone response elements are promoter proximal
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What you need to know Chromatin remodeling
complexes can change chromatin structure
locally to make promoter accessible to polymerase
complex, rule of thumb is Open chromatin gene
ON Condensed chromatin gene OFF Transcription
factors can have activator or repressor domains.
Activator domains recruit HATs to further open up
chromatin, whereas repressors recruit HDACs to
keep DNA wound up tight in nucleosomes. Nuclear
hormone receptor family is an example of
transcription factors that can be both activators
(when bound to ligand) or repressors
(hetero- dimeric receptors are constitutively in
the nucleus and repress genes in absence of
ligand). Regulatory elements can be close by or
as far as 50 kb away from 1, they include
enhancers that are regulated during development.