Epigenetics, brain function, and evidence of its control. Flashcards
How do pluripotent cells (neural progenitors) become neurons and glia? Epigenetics and OCT4.
Neural progenitors differentiate during development, requiring temporally regulated waves of gene expression that are regulated, in part, by epigenetic mechanisms. OCT4 is the master plyripotency gene, and its activation is necessary for maintaining pluripotency, whereas it must be actively silenced through methylation for the cell to differentiate.
Brief outline of epigenetic process in neurons throughout specialisation.
- General condensation of chromatin in early stage of specialisation.
- Increased hydroxymethylation in neurons,
- Increased MeCP2 bindings.
Histone acetylation in later neurons.
At what point is the genome most susceptible to epigenetic modifiers. What are the potential consequences in modifier errors.
The foetal genome is most susceptible to epigenetic modifiers in the maternal environment. Errors may lead to abnormal phenotypic outcome.
What is imprinting? How is it regulated?
An epigenetic mechanism resulting in parental expression of certain gene- genes that are epigenetically marked such that they are monoallelically expressed in a parent-of-origin dependent manner. It is regulated by DNA methylation, resulting in expression of either the maternal or paternal allele. Most imprinted genes contain differently methylated regions which differ methylation between the paternal and maternal alleles. This variation allows for differential regulation of these alleles dependent on parental origin of the allele and may result in either active transcription or preferential silencing of genes.
Why are imprinted genes particularly vulnerable to error?
The monoallelic expression of imprinted genes makes then vulnerable since a mutation/deregulation of the expressed allele cannot be compensated for by the other allele.
How do ARTs increase the risk of error? (mRNA splicing, errors, Whitelaw et al., 2014; differential allelic expression in early embryo; Kohda & Ishino, 2013).
ARTs such as ICSI and IVF can cause epigenetic changes such as aberrant DNA methylation, and hypermethylation of certain genes (indicating mRNA splicing errors; Whitelaw et al., 2014) such that there is differential allelic expression in the early embryo (Kohda & Ishino, 2013). This may go some way towards explaining why ART can increase the risk of adverse pregnancy outcomes and imprinting errors resulting in incorrectly silenced genes. Related to Angelman & Prader-Willi Syndromes.
How is 15q11-13 controlled by SNRPN (Chamberlain & Lanade, 2010)
o In this cluster, the expression of imprinted genes is controlled by differential DNA methylation at the imprinting centre in the SNRPN gene (Chamberlain and Lanande, 2010).
- One element silences some of the paternal alleles in the cluster.
- The other silences some of the maternal alleles.
What are the symptoms of Angelman syndrome? What abnormalities exist at the cortical level (Davies et al., 2000)?
o Mental retardation, an inappropriate happy demeanour, dysmorphic facial features.
At cortical level, exhibit mild cortical atrophy and aberrant cerebellar morphology (Davies et al., 2000)
What causes it? Imprinting defects deletion/loss of function of maternal UBE3A, point mutations, uniparental disomy. Severity moderated by number, suggesting adjacent modulation (Kopsida et al., 2011). 5% imprinting defect.
o Caused by abnormalities (imprinting defects, deletion/loss of function of the maternally expressed UBE3A gene, point mutations, and uniparental disomy) in chromosome 15q11-13, while the paternal allele is suppressed. Those with deletions spanning multiple genes adjacent to UBE3A exhibit greater symptom severity than those with point mutations of, implying adjacent genes modulate the AS phenotype (Kopsida et al., 2011). Fewer than 5% cases are associated with an imprinting defect.
Angelman case studies of ICSI, methylation loss (on 15 & SNRPN, Cox et al., 2002; Orstavik et al., 2003). Implications if <5% imprinted.
o Case studies of patients with Angelman syndrome conceived with ICSI have found aberrant loss of methylation on 15 and at the SNRPN locus (the imprinting centre controlling the expression of 15q11-13- one element of the centre silences some of the paternal alleles while the other silences some of the maternal alleles) (Cox et al. 2002; Orstavik et al. 2003). With imprinting defects only accounting for <5% cases, there is a concern of over-representation of imprinting defects among those conceived by ICSI.
Prader-Willi S. Symptoms? (Davies et al., 2008: endocrine anormalities: hypothalamic insufficiency)
o Mild mental retardation, neonatal hypophagia followed by voracious appetite in early childhood, hypogonadism, and multiple endocrine abnormalities related to hypothalamic insufficiency (Davies et al., 2008).
PWS causes? Deletion of paternally inherited region (65-70%), mUPD (25-30%) or SNRPN abnormalities (2-5%).
o Results from deregulation of paternally expressed genes at 15q11-q13 that would, under normal conditions, be silenced in the maternal allele. In this respect, the genetic level it is the sister disorder of AS. This loss may arise due to deletion of the paternally inherited region (65-70% of cases), uniparental duplication of the maternally inherited region (mUPD: 25-30% cases), or imprinting centre abnormalities (2-5% cases).
What do the behavioural phenotypes of AS/PWS suggest of the normal functions of these particular imprinted genes?
• Behavioural phenotypes of both AS and PWS suggest that imprinted genes may affect both primary-motivated behaviours and higher-level cognitive functions (though cannot ignore possibility of contributions from abnormal expression of non-imprinted brain-expressed genes).
Why are eusocial insects such as honeybees good for addressing epigenetic questions? (dramatic caste polyphenisms –> tied to differential methylation, bimodial Cp6 richness (high/low methylation).
Eusocial (i.e. complex social systems, with division and cooperation of reproductive labour with a caste-specific phenotype) insects are great for addressing questions about epigenetics because they have dramatic caste polyphenisms that appear to be tied to differential methylation, DNA methylation is widespread in various groups of social insects-, and there are intriguing connections between the social environment and DNA methylation in many species, from insects to mammals. Compared to fruit flies or mosquitoes, honeybees hve substantial DNA methylated, but a bimodal distribution of CpG richness, suggesting that some are highly methylated, and others are non-methylation/weak methylation.
Why may eusociality of honeybees be problematic however?
Eggs are often laid directly into “queen cups” by the queen, but workers may also move eggs to the cups or destroy queen larvae/pupae already in them. Due to the queen’s promiscuity, a honeybee hive typically contains multiple worker subfamilies, and often some are overrepresentative compared to others due to preferential feeding of some and selective abortion of others. The implication of this is that while the provision of epigenetic factors via larval nutrition (i.e. feeding of royal jelly) is the main epigenetic influence on queen maturation, this might in turn be controlled by genetic factors that control provisioning and egg-caring behaviour in the workers.
