Epigenetics Flashcards
epigenetics
molecular switches and markers that help control gene regulation that sits on top of the genome
3 categories- DNA methylation, Histone modifications, miRNAs
DNA methylation
enzyme mediated chemical modification adds a methyl group which does not allow transcription factors easy access to DNA
usually happens at C preceding a G- CpG sites that form CpG islands
located in the promotor region- important for regulation
methylation silence the gene- usually unmethylated
Histone modification
acetylation of histones leads to activation
miRNAs
small non coding RNAs
12-13 nts long
single standed
highly conserved
complementary binding to mRNA- results in translational repression or cleavage
each tissue has a characteristic expression profile. related tissues have similar profiles
tissue specific methylation
methylation patterns cause certain tissues to express specific genes- cellular differenation
methylation profiles are inherited thru divisions
genomic imprinting
we only inherit one working gene
epigenetic tags stay for the lifetime of the organisms
certain genes are always silenced in the egg, some always in the sperm
miRNAs in neoplastic tissue
miRNAs are differentially expressed
selective miRNAs are up or down regulated in all tumors
other miRNAs are affected only in specific tumor types
prader-willi syndrome
mental retardation, short stature, hypotonia, hyperphagia, obesity, small hands and feet
active prader willi found on paternal
deletion of paternal prader willi leads to prader willi syndrome b/c it is imprinted in females
angelman syndrome
mental retardation, inappropriate laughter
active angelman gene found on maternal
deletion of maternal angelman gene leads to angelman syndrome b/c paternal copy is imprinted
fragile x syndrome
trinucleotide repeat disorder (CGG) in the FMR-1 gene
causes mental retardation, broad forehead, long face
severity related to # of repeats
expanded number of repeats causes methylation and gene silencing
epigenetics and cancer characteristics
hypermethylation of tumor suppressor genes (BRCA1 in breast cancer, Rb in retinoblastoma, p16 in solid tumors, p15 in acute leukemia)
global hypomethylation
persistence of methylated C residues causes spontaneous mutations to T base (p53)
MGMT
DNA repair protein that removes mutagenic and cytotoxic adducts
in gliomas, MGMT will remove potentially therapeutic alkyl agents, and tumor cells do not respond
therefore, test for MGMT to identify therapeutics
candidates: non small cell lung cancer, head and neck, colorectal carcinoma
colorectal cancers
MMR genes can be hypermethylated
needs to be bilateral for sporadic cancer
in familial, one “hit” is already inherited
MDS and hypermethylation
abnormal methylation of tumor suppressor genes
associated w/ progression to
AML and resistance to conventional chemotherapy
decitabine- hypomethylating drug used to treat MDS by covalently binding DNMT, and after several cellular divisions normal methylation is resumed
HDAC inhibitors- similar to decitabine, but with histones
detection of DNA methylation
testing for CpG methylation in tissue DNA is important for
tumor detection
outcome prediction
treatment selection
assessing efficacy
majority of methods start w/ conversion of unmethylated cytosine to uracil
amplified by PCR- only the methylated cytosines remain
