The Significant Rise of Neuronal Epigenetics: A Focus on Adult
Neurogenesis
Daniel Tagg - 89555
Final Year Project – Presentation 3 May 2023
Epigenetic and Adult Neurogenesis: a combined history
(Holliday, 2006)
Pre 1900's
Mendel's work on
Heritability
1939Waddington
coins term
'epigenetics'
1969Griffith discovers DNA
methylation
1974Arber links DNA
methylation to
gene regulation
!980Chromatin st
ructure
predicted
!990s onward
s
Explosio
n in
epigenetic r
esearch
1998
Eriksso
ns disc
overy
of
adult neurogenesis
in
humans provid
es
conclu
sive proof o
f the
concept &
signals
the end
of the previo
us dogma
1979
Kapman limits
the exte
nt of a
dult
neurogenesis
to th
e olfacto
ry bulb
& dentate gyrus o
f rodents
1962
Altman provid
es first
experim
ental proof o
f
adult n
eurogenesis
1928
Cajal proposes t
hat
neurogenesis
is lim
ited
to early deve
lopment
• Working definition of epigenetics:– “Heritable changes in patterns of gene expression that are not encoded in the primary
DNA sequence itself”• DNA methylation
– Occurs predominantly on cytosine residues , ‘CpG islands’– Involved in Genomic ‘imprinting’ , X chromosome inactivation– DNA methyltransferases catalyses this methylation – Active DNA demethylation in mammals ?
• Chromatin modifications– 0ver 60 known residue modifications, some repressive, some activating, some both?– Histone acetyltransferases, methylation…….– ATP dependent remodelling complexes
• Non coding RNA (ncRNA)– ‘fine tune’ gene expression networks– The greatest subset of epigenetic factors.– Numerous types of ncRNA including; micro (miRNA), short interfering (siRNA)……
Epigenetic regulatory mechanisms
(Kouzarides, 2007)
Adult neurogenesis: overview
Key:
'non-neurogenic'
'neurogenic'
‘limited evidence/ controversial'(Gould, 2007)
• Within the two defined regions, adult neural stem cells (NSCs) are present.
• Adult neurogenesis mimics embryological neurogenesis.• It therefore goes through the following stages:
– Stem cell maintenance and proliferation– Fate specification– Migration– Survival– Neuronal maturation and integration
• Each one of these stages involve a variety of molecular mediators released from the ‘neurogenic niche.’
• These signals can be broadly divided into two groups: – Intrinsic – produced by NSCs and progenitors, (mostly transcription factors)– Extrinsic – produced by surrounding glia and endothelial cells. Such ‘niche’ signals
include neurotransmitters, growth factors, hormones, and injurious stimuli.
Adult neurogenesis: Regulated at every step
(Alvarez-Buylla, 2004)
• The majority of the evidence gathered for this project was derived through subject specific searches on PubMed & Web of knowledge/science.
• The following search term was used:– (neuronal OR neural OR nerve OR neurone OR neurones) AND (epigenetics OR epigenetic OR DNA
AND methylation).
• The number of results for each search were then limited at 5 year intervals and recorded for the date range of 1940 to 2015 (2011).
• From knowledge of previous bibliographic studies the increase in publications was predicted to exhibit an exponential relationship of the following standard form:
– Where P = the number of publications, P0 = the starting amount, r is the denoted growth constant, t represents time, and e is a mathematic constant.
• Thereafter, statistical analysis (SPSS) was performed in order to ascertain the validity of this model.
Data collection & analysis
Neuronal epigenetics: Exponential growth in literature
R2 = 0.9907
• What does this signify?
Epigenetic modifiers of adult neurogenesis – SVZ
(Sun, 2011)
?
Cortex
?
OB
RMS
SVZHipp
DG
Epigenetic modifiers of adult neurogenesis – SGZ
(Sun, 2011)
• Epigenetic regulatory mechanisms are dynamic, and therefore heritability is an unknown quantity in this regard.
• Adult neurogenesis essentially mirrors the latter stages of embryological neurogenesis and is controlled by its neurogenic niche.
• Environmental stimuli including neuronal activity can lead to the transduction of phenotypic changes though specific epigenetic mechanisms.
• Importantly, epigenetic regulatory mechanisms are involved in every stage of adult neurogenesis.
• It is useful to view epigenetic modifications as fine tuning mechanisms of gene transcription.
• Of the epigenetic modifiers ncRNAs are perhaps the most interesting.
Neuronal epigenetics: general and emerging concepts
Future Research Directions & Questions ?
To what extent are epigenetic modifications heritable - which specific modifications & at which gene loci?
What molecular mediators lead to the occurrence of adult neurogenesis outside the two consensus regions?
To what extent do ncRNAs determine the specificity of epigenetic factors?
What determines which gene loci are dynamically regulated and what are the temporal and spatial elements to this?
What factors are preventing the translation of neuronal epigenetic research into treatments?
(Key references – in order of appearance)•Holliday, R. 2006. Epigenetics: a historical overview. Epigenetics, 1, 76-80.•Kouzarides, T. 2007. Chromatin modifications and their function. Cell, 128, 693-705.•Gould, E. 2007. How widespread is adult neurogenesis in mammals? Nat Rev Neurosci, 8, 481-8.•Alvarez-Buylla, A. & Lim, D. A. 2004. For the long run: maintaining germinal niches in the adult brain. Neuron, 41, 683-6.•Sun, J., Ming, G. L. & Song, H. 2011. Epigenetic regulation of neurogenesis in the adult mammalian brain. Eur J Neurosci, 33, 1087-93.
References
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