Exam 5: Epigenetic Phenomena Flashcards
5-azacytidine
DNA methyltransferase (DNMT) inhibitor that causes hypomethylation of the genome
potential to counteract malignancies associated with hypermethylation
therapy for acute myeloid leukemia
Angelman syndrome (AS)
caused by deletion on maternal chromosome 15
unusual facial features, seizures, movement and gait disorders, severe mental retardation
(parent of origin effect)
Beckwith-Wiedemann Syndrome (BWS)
uniparental disomy
child inherits both homologues of a portion of chromsome 11 from father
overabundance of insulin-like growth factor 2 - leads to kidney, adrenal, and liver problems resulting in severe hypoglycemia
susceptibility to childhood cancer
Boundary elements
chromatin barriers
separates active and inactive genomic regions - stops spread of inactivation region caused by cytosine methylation self-propagation
chromatin barriers
boundary elements
stop spread of inactivated region of DNA (caused by cytosine methylation) and separates active and inactive genomic regions
CpG islands
clusters of CpG dinucleotide repeats close to 5’ region of genes
generally unmethylated
CpG dinucleotide repeats are very susceptible to methylation - methylation of CpG islands shut down expression of neighboring genes
CpG dinucleotide repeat
very susceptible to methylation on cytosine residues - silences chromosomal region
about 70% in human genome are silenced by methylation - includes highly repetitive DNA, telomeres, and centromeres
de-novo DNA methylation
methylation of unmethylated cytosine bases of DNA
introduced into unmethylated strand of DNA by DNA methyltransferases DNMT3a and b
DNA methyltransferase (DNMT) inhibitors
inhibitor that causes hypomethylation of genome - counteracts malignancies associated with hypermethylation
therapy for acute myeloid leukemia
5-azacytidine
DNA methyltransferase DNMT1
maintains pattern of DNA methylation throughout mitosis
during DNA replication, non-methylated strand is synthesized on methylated template strand
non-methylated strand is methylated by DNMT1
epigenetics
study of stable, heritable changes in gene expression that do not involve changes in DNA sequence
important for: imprinting during development & gametogenesis, inactivation of X-chromosome, and progression of cancer
genomic instability
can be caused by hypomethylation (de-methylation of silent chromatin) - initiating transformation of a cell into a tumor cell
leads to somatic recombination - Non-homologous recombination
leads to drastic increase in mutations in established tumor
histone acetyltransferases (HATs)
acetylates histones, decreasing their binding affinity to DNA and facilitates transcription
Histone modification
histone de-acetylase (HDAC) inhibitors
promote histone hyperacetylation and gene re-expression in chronic lymphocytic leukemia
hypomethylation
lead to expression of genes in normally silent regions of genome
leads to re-expression of silenced genes and expression of endogenous retroviruses
reactivate transposable elements - leads to somatic recombination and genomic instability
histone deacetylases (HDACs)
remove acetyl groups from histones
favors binding of histones to DNA (increases binding affinity), leading to chromatin condensation & silencing of transcription
histone methylases
bind to HP1 proteins that are bound to methylated histones (after de-acetylation of histones)
methylation of histones spread long chromosomes until a boundary element is reached
methylases allow chromatin inactivation to spread
HP1 proteins
bind to methylated histones after histones have been de-acetylated
bind histone methylases to spread chromatin inactivation
hypermethylation
shuts down expression of genes close to CpG islands
silences gene transcription
may cause cancer by silencing tumor suppressor genes
maintenance of DNA methylation
maintained through mitosis by DNA methyltransferase DNMT1 by methylating non-methylated strand after DNA replication
methylcytosine binding proteins (MBPs)
binding brings about repression of transcription
occurs after a stretch of DNA has been methylated by DNA methyltransferases
interact with repressors of transcription (blocks transcription of nearby genes) & histone deacetylases (HDACs) (remove acetyl groups from histones leading to chromatin condensation/inactivation of transcription)
parent of origin effect
inheritance of genetic variation from the mother or father
certain genes expressed due to imprinting - phenotypic variation
Prader-Willi syndrome (PWS)
deletion on paternal chromosome 15
characterized by obesity, excessive food seeking behavior, hypogonadism and mental retardation
(parent of origin effect)
retrotransposons in human genome
transcriptionally inactive DNA
mobile genetic elements that could cause mutations/disease if not silenced by methylation
about 45% of human genome derived from retrotransposons of viral origin
silenced by methylation
uniparental disomy
abnormality where rescue of an aneuploid zygote where surplus chromosome is lost & rescued zygote retains both chromosomes from same parent
can lead to a situation in which an individual has only maternally or only paternally imprinted homologues of a chromosome
Can lead to problems with gene dosage - overabundance on one gene and lack of another
X-chromosome inactivating center (XIC)
contains XIST (inactive X-specific transcript) gene - gets transcribed on X-chromosome to be inactivated inactivation of X-chromosome proceeds via imprinting
XIST (inactive X-specific transcript)
in XIC of X-chromosome, gene transcribed on X-chromosome to be inactivated
RNA associates closely with X-chromosome and mediates inactivation of most of the chromsome
DNA and histones on X chromosome to be inactivated are methylated - shuts down expression of most genes
heterochromatin
tightly packed DNA - histones are deacetylated & methylated, DNA methylated - transcription silenced
euchromatin
loosely packed DNA - histones acetylated, DNA not methylated - transcriptionally active
imprinting
form of DNA silencing, shuts down certain chromosome regions & maintained throughout mitosis
marks chromosome as having come from father or mother - some genes are repressed of maternal chromosome while others of paternal
takes place during gametogenesis - imprinting center (silences chromosomal regions by DNA methylation and histone deacetylation)
Imprinting important in 2 biological processes:
Development - cell type specific imprint established
Maturation of gametes - gametogenesis, parent of origin specific imprint imposed on chromosomes (make all inherited chromosomes look either maternal or paternal)
Cancer can result from hypo or hypermethylation by:
hypomethylation - demethylation (& overexpression) of oncogenes, expression of silent chromatin - somatic recombination, increase in mutations
hypermethylation - silencing of tumor suppressor genes
