Epigenetics 2 Flashcards
What does MeCP2 bind to and what is its effect?
Methylated C bases Recruits cofactors (transcriptional repressors) - remove acetyl groups from histone tails - further compacts chromatin
Which disorder is MeCP2 implicated in?
Rett syndrome
What are the symptoms of Rett syndrome?
Normal development until 6-18 months
Regression - walking, speech, social skills
Hand stereotypies develop (grasping)
Which chromosome is MeCP2 located on?
X chromosome
What is the role of MeCP2 in resting neurons?
Transcriptional repressor
How is MeCP2 affected in active neurons?
Activity-induced MeCP2 phosphorylation - released from chromatin - activates gene expression
How does MeCP2 mutation lead to Rett syndrome?
Partial/complete loss-of-function of protein
Inappropriate transcription of genes at critical times in brain development
Which offspring genes are affected by rat stress during pregnancy and how?
Increased DNA methylation of BDNF - decreases BDNF expression - BDNF role in synaptic plasticity
Decreased CRH methylation - increases HPA responsiveness and anxiety behaviour to acute stress
Which gene is affected by early stress in rats, affecting the adult HPA axis and how?
Increased licking and grooming of pups - increases Nr3c1 expression
Non-epigenetic - increases 5HT release - increases 5HT7R stimulation - increases NGF1-A expression in hippocampus - trnascriptional activator for Nr3c1
Epigenetic - demethylation of Nr3c1 exon1 and acetylation of histones around Nr3c1
Increases Nr3c1-driven GR expression in hippocampus - lower glucocorticoid levels in response to stress and increased grooming behaviour as mothers
Which environmental factors can alter epigenome?
Nutritional Maternal stress during pregnancy Maternal drug abuse Maternal smoking Insufficient maternal care Childhood trauma
What is the role of FKBP51?
Decreases glucocorticoid binding to GR
What is the effect of early life stress in those with FKBP51 risk allele?
FKBP51 DNA demethylation
Large increase in FKBP51 production in response to adult stress
Increased resistance to cortisol - hard to switch off stress response
What is the role of xCT?
Glutamate exchanger in astrocytes and microglia - mediates glutamate release from these - controls synaptic cleft glutamate levels
What is the effect of stress on xCT?
Decreases histone acetylation in xCT - decreases expression in ventral dentate gyrus
Decreases glutamate release via xCT
Decreases neuronal presynaptic mGlu2 activation (inhibitory autoreceptors) - excess glutamate release - loss of resilience to stress
