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