Adv. pathophysiology (Epigenetics)

Methylation

-DNA methyltransferases (DNMTs) carry out methylation of cytosine -addition of a methyl group to a cytosine -methylation takes place between cytosine and a guanine base = CpG dinucleotide -method of silencing gene expression

Acetylation

-DNA negatively charged -due to negatively charged phosphate backbone -positively charged lysine on histone attracts the negatively charged phosphate on DNA, this attraction causes the DNA to be compacted against the histones -acetylation of histone proteins allow the DNA to remain negatively charged. -lysine attaches to acetyl -results in negatively charged DNA to be able to attract to the transcription factor -in lysine and arginine

MBD

-Methyl binding domain proteins -MBD sits on the regions that are heavily methylated -MBD prevents the transcription factors and prevents transcription

X chromosome inactivation

-X have many essential genes compared to Y -XX can have toxic double dose of X linked genes --> females transcriptionally silence one X chromosome (extensive methylation and hypoacetylation) -silences X chromosome is a barr body

CpG islands

-accumulation of CpG dinucleotides near the promotor region --> DNA methylation is influential

Rubinstein-Taybe Syndrome

-caused by mutation in CREBBP and EP300 HAT proteins --> causes hypoacetylation -decrease in transcription, thick chromatin

Types of epigenetic modification

-chemical tags -DNA methylation -histone acetylation -non coding RNA -miRNAs -Linc's -inheritance, environmental factors, diet, chemicals affect epigenetics

calico cats

-coat colors in X chromosome random inactivation of X chromosomes --> color blotches

Deacetylated chromatin

-compact -transcriptionally inactive -HDACs

X chromosome deactivation

-females have 2 X's -only one X is transcriptionally active -the other chromosome is selected for epigenetic silencing and becomes heavily acetylated and methylated

Genomic imprinting

-gene silencing -diseases can occur from abnormal imprinting

HATs

-histone acetyltransferase -adds acetyl group to the histone proteins

HDACs

-histone de-acetylase -removes an acetyl group

Histone methylation

-in lysine and arginine -the effects are not straightforward

Prader-willi

-inherited from father -obesity -deletion of the same gene in long arm of Chr 15

Angelman

-inherited from mother -seizures, mental retardation -deletion of the same gene in long arm of Chr 15

5-azacytosine

-inhibits DNMTs -covalently bonds with DNMT and messes up the methylation process -risk of mutation -only prevents methylation, it doesn't reduce existing methylation -cancer is a result of methylation -would not work on a disease with a long term methylation

CpG dinucleotide

-methylation between cytosine and guanine

Acetylated Chromatin

-not compact, open -transcriptionally active (space for transcriptional factors to activate transcription) -HATs

Beckwith-wiedemann syndrome

-overgrowth condition -presdisposition to cancer -IGF2 gene active on paternal but inactivated in maternal -one normal active copy of IGF2 (paternal)

Heavily methylated promoter area

-reduces transcription of that particular gene

miRNA

-short nucleotide derived from intergenic and intronic DNA -regulate translation by forming dsRNA -regulates 50% of translation -4%of genome is miRNAs

Q. why dont females have more X linked disorders?

-some degree of gene transcription is still possible even though it is heavily methylated

Epigenetics

-the study of environmental influences on gene expression that occur without a DNA change -change in phenotype but not genotype