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5 - Epigenetic regulation of gene expression, Bird & Jaenisch.doc

5 Pages
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Department
Biology
Course Code
BIOLOGY 3UU3
Professor
David Rollo

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Article #5
Cells of a multicellular organism are genetically homogeneous, but structurally
and functionally heterogeneous b/c of different gene expression
Epigenetics or “outside conventional genetics” - describes the study of stable
alterations in gene expression potential that arise during development & cell
proliferation
Such epigenetic processes are essential for development & differentiation, but
they can also arise in mature humans & mice, either by random change or under
environ influence
also guard against viral genomes that would otherwise hijack cellular fn
modification of DNA or proteins are recognized by specific proteins that
recognize modifications and facilitate the appropriate biological effects
Establishing and maintaining patterns of DNA methylation
DNA methylation
o chief contributor to stability of gene expression states, might be
responsible for stable maintenance of particular gene expression pattern
through mitotic cell division and is involved in maintaining X
chromosome inactivation in females
oDNA methylation est. a silent chromatin state by collaborating with
protein that modify nucleosomes
oPost replication modification
oDNA methylation found in cytosines of the dinucleotide sequence CpG
Extent of DNA methylation changes during mammalian development:
oWave of demethylation during cleavage
oGenome wide methylation after implantation
oDemethylation is an active process that strips the male genome of
methylation within hours of fertilization.
oMaternal genome is only passively demethylated during cleavage
divisions
omethylation decreases in specific tissues during differentiation
omethylation occurs rarely in postgastrulation – but is seen in cancer!
DNA methyltransferases (DNMT):
DNMT1 maintenance methylrtansferase (i.e. maintains but not
est maternal imprint), absence results in global demethylation and embryonic
lethality, DNMT1o responsible for maintaining, but not establishing
maternal imprints
DNMT3a, DNMT3b methylation after implantation,
expressed highly during developing embryo
DNMT3L no DNMT activity on own but joins to DNMT3a/b to
imprint on female germ line
DNMT2 no DNMT alone, may be responsible for small amount
of non-Cpg methylation in flied
DNA meth is essential for vertebrate development
Loss of methylation causes apoptosis in embryos/fibroblasts, NOT in stem cells,
or cancer cells, depression of extopic gene expression, and transcriptional
activation of transposable elements
Evolution explanation of methylation mechanism to silence transposable
elements? Mediate transcriptional noise reduction? Yet to be resolved
Non embryonic cells 80% CpG’s are methylated
CpG islands are associated with genes and all may contain promoters
methylation is interrupted by short CpG islands generally unmethylated all the
time (few exceptions), if methylated leads to long term shut down of the gene
cancer cells methylation of CpG islands can contribute to gene silencing
histone modifications may also tirigger methylation of DNA
DNA methylation acts as a system of cellular memory that isn’t directly involved
in intiating gene silencing, but senses and propogates the silent state
Methyl-CpG-binding domain proteins (MBDs) like MeCP2 recruit chromatin
remodelling things…
Histone deacetylation (HDAC’s)
SO….methylation doesn`t directly shut off genes, it does so my recruiting other
genes that affect histone modification such as deacetylases!!!!
DNA methylation is just one component of a wider epigenetic program that
includes other postsynthesis modifications of chromatin make feedback loops
so ensure the polarization of chromatin domains so that self-reinforcing steps are
present to prevent going in other direction (pulls back to “pole”)
Interpreting the DNA methylation signal
Several ways that methylation can repress transcription:
1. exclusion of proteins that affect transcription by the methylation blocking
their binding sites
oCpG methylation blocks the binding of chromatin boundary
element binding protein (CTCF – blocks interactions between
promoter and enhancer)
2. Methyl-CpG-binding domain proteins (MBDs):
oDNA methlylation is repulsive to some DNA binding proteins
but attractive to others
omediators of transcriptional repression
oIncludes MeCP2 and MBD 1-4
oTransciptionally repress MeCP2 interacts with a corepressor
complexes containing HDAC’s (histone deacetylases)
shows that there is an interaction between DNA methylation
and histone modification

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Description
Article #5 • Cells of a multicellular organism are genetically homogeneous, but structurally and functionally heterogeneous b/c of different gene expression • Epigenetics or “outside conventional genetics” - describes the study of stable alterations in gene expression potential that arise during development & cell proliferation • Such epigenetic processes are essential for development & differentiation, but they can also arise in mature humans & mice, either by random change or under environ influence • also guard against viral genomes that would otherwise hijack cellular fn • modification of DNA or proteins are recognized by specific proteins that recognize modifications and facilitate the appropriate biological effects Establishing and maintaining patterns of DNA methylation • DNA methylation o chief contributor to stability of gene expression states, might be responsible for stable maintenance of particular gene expression pattern through mitotic cell division and is involved in maintaining X chromosome inactivation in females o DNA methylation est. a silent chromatin state by collaborating with protein that modify nucleosomes o Post replication modification o DNA methylation found in cytosines of the dinucleotide sequence CpG • Extent of DNA methylation changes during mammalian development: o Wave of demethylation during cleavage o Genome wide methylation after implantation o Demethylation is an active process that strips the male genome of methylation within hours of fertilization. o Maternal genome is only passively demethylated during cleavage divisions o methylation decreases in specific tissues during differentiation o methylation occurs rarely in postgastrulation – but is seen in cancer! • DNA methyltransferases (DNMT):  DNMT1 maintenance methylrtansferase (i.e. maintains but not est maternal imprint), absence results in global demethylation and embryonic lethality, DNMT1o  responsible for maintaining, but not establishing maternal imprints  DNMT3a, DNMT3b  methylation after implantation, expressed highly during developing embryo  DNMT3L  no DNMT activity on own but joins to DNMT3a/b to imprint on female germ line  DNMT2  no DNMT alone, may be responsible for small amount of non-Cpg methylation in flied • DNA meth is essential for vertebrate development • Loss of methylation causes apoptosis in embryos/fibroblasts, NOT in stem cells, or cancer cells, depression of extopic gene expression, and transcriptional activation of transposable elements • Evolution explanation of methylation  mechanism to silence transposable elements? Mediate transcriptional noise reduction? Yet to be resolved • Non embryonic cells  80% CpG’s are methylated • CpG islands are associated with genes and all may contain promoters • methylation is interrupted by short CpG islands  generally unmethylated all the time (few exceptions), if methylated leads to long term shut down of the gene • cancer cells  methylation of CpG islands can contribute to gene silencing • histone modifications may also tirigger methylation of DNA • DNA methylation acts as a system of cellular memory that isn’t directly involved in intiating gene silencing, but senses and propogates the silent state • Methyl-CpG-binding domain proteins (MBDs) like MeCP2 recruit chromatin remodelling things… • Histone deacetylation (HDAC’s) SO….methylation doesn`t directly shut off genes, it does so my recruiting other genes that affect histone modification such as deacetylases!!!! • DNA methylation is just one component of a wider epigenetic program that includes other postsynthesis modifications of chromatin  make feedback loops so ensure the polarization of chromatin domains so that self-reinforcing steps are present to prevent going in other direction (pulls back to “pole”) Interpreting the DNA methylation signal • Several ways that methylation can repress transcription: 1. exclusion of proteins that affect transcription by the methylation blocking their binding sites o CpG methylation blocks the binding of chromatin boundary element binding protein (CTCF – blocks interactions between promoter and enhancer) 2. Methyl-CpG-binding domain proteins (MBDs): o DNA methlylation is repulsive to some DNA binding proteins but attractive to others o mediators of transcriptional repression o Includes MeCP2 and MBD 1-4 o Transciptionally repress MeCP2 interacts with a corepressor complexes containing HDAC’s (histone deacetylases)  shows that there is an interaction between DNA methylation and histone modification o mice without MBD2 are viable and fertile but lack methylating DNA binding complex MeCP1  defective in the methylation- mediated of genes and significant gene depression - MBD proteins then recruit additional proteins to the locus, such as histon
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