LSM1102 CA1 Reference Paper summary

1. This paper is about how chromosomal structure (especially

heterochromatic regions) , transposable elements and epigenetics, relate
to aging
2. Terms
a. Deleterious effects
i. Harmful effects to health
b. Histone methylation/ acetylation
i. Changes to histone that can either increase or decreases
access depending on amino acid affected
3. How heterochromatin damage affects ageing
a. Deleterious effects on cellular homeostasis
i. Aberrant expression of normally repressed genes
Transcriptional noise may cause cumulative harm by
using up cellular factors needed for transcribing normal
genes
Genes no longer repressed may express genes that
cause aging phenotypes
ii. Redirection of limited energy towards repair/ maintenance of
damaged genes
4. Epigenetics also affect aging
a. Histone modification (acetylation, methylation etc)
i. In yeast, as H4K16 acetylation increases, Sir2 levels
decreases
Sir2 is a deacetylase, thus genes are less expressed
ii. In worms
Knockdown of H3K4 methyltransferase increases
lifespan
Knockdown of H3K4 demethylase decreases lifespan
Thus excessive H3K4 trimethylation is detrimental to
lifespan
It is a hallmark of actively transcribed chromatin
So the genes transcribed cause aging phenotype
Such knockdown is heritable
Other knockdown of H3K27me3 demethylase UTX-1
increases lifespan
H3K27me3 marks increases
Thus less transcription
Contrasts with the other demethylase
knockdown
iii. In drosophila
Marks, H3K4me3 and H3K36me3, indicating active
chromatin decrease with age
Decreased HP1 expression correlates with shortened
lifespan
Has premature muscle degeneration
Has large increase in rRNA transcripts
Sign of large volume of transcrtption
Increased HP1 expression correlated with increased
lifespan

 Has increased muscle structure and function

Has less rRNA transcripts
Decrease in H3K27 methylation increase lifespan
Contrasts with effect in worm
Chromatin marks may be processed differently
in different tissues or species, thus affecting
aging differently.
iv. In mouse
As mouse age, there is a general decrease in histone
acetylation and increase in histone methylation
Hypoacetylation of H4K12 lead to concomitant
failure to express a gene necessary for memory
consolidation
Treatment with histone deacetylatase inhibitors
restored gene expression profile and learning
behaviour
Reduced acetylation of H3K9 and H4K12 also led
to reduced gene expression important for longterm potentiation
Treatment with histone histone deacetylatase
inhibitors also raised acetylation levels and
reduced LTP decline
Changes in DNA methylation patters are consistent
over several tissue types
EE paradigm increases learning and memory
Correlates to increase in histone acetylation and
methylation on different residues on H3 and H4
Histone deacetylase inhibitor also benefits
Mouse modules for Alzheimers showed a decrease in
H4 acetylation, correlated with defective LTP and
memory formation
Again, inhibitor treatment helps
Mouse module for Hutchinson-Gilford progeria (rapid
aging) has hypoacetylated H4K16, correlates to
defective lamin A processing and short lifespan
Treatments include overexpression of histone
acetyltransferace Mof or chemical inhibition of
deactylase
Contrasts with yeast where acetylation increases with
age
b. Loss of histones in heterochromatic region
i. Decrease in silencing, problems above
c. Loss of histone chaperone
i. Chaperones binds to histone and regulate nucleosome
assembly
Affects gene expression
d. In yeast, countering a natural decrease in histone protein levels, led
to longer life
i. Knock out HIR1, a histone transcription repressor
ii. Overexpress H3 and H4 histone genes
5. Replicative senescence are correlated with

a. Decrease in histone levels

b. Locations of histone methylation an acetylation are redistributed
c. Formation of dense non-pericentromeric (not near centromere)
heterochromatin
i. Aka DNA bunches up at locations not near centromere
ii. Detected by higher levels of methylated histones H3K9me3,
H3K27me3
d. Weaker DNA packing
i. Regions of open and closed chromatin are less distinct and
look more similar
e. Reversal of gene expression
i. Promoters and enhancers of active genes become more
closed
ii. Normally silent heterochromatic regions become more open
6. Chromatin position also affects aging
a. In yeast
i. Heterochromatic telomere regions are near the nuclear
envelop
ii. Silencing of chromatin occurs when it is closer to the nuclear
periphery and vice versa
b. In higher eukaryotes
i. Heterochromatic regions usually contain Lamin-associated
domains that bind to the nuclear lamina
Correlation of poor gene transcription with proximity to
lamina
ii. Transcriptionally active euchromatin regions are found in
distinct areas inside the nucleus, caked transcription factories
iii. The mutation of lamin A can lead to misshapen nuclei that
changes heterochromatin organisation, leading to defects in
DNA replication and transcription
iv. Lamin B1 expression naturally decreases with age
Knocking down the expression causes early entry into
senescence and reorganisation of LAD chromatin
structure.
7. Transposable elements can have deleterious effects when expressed
a. They are widely transcriptionally expressed and can regulate nearby
genes
b. Types of transposons
i. Retrotransposons gets transcribed, encodes its own reverse
transcriptase, gets reverse transcribed and then integrated
into a new location
Copy and paste
ii. DNA transposons are flanked by inverted repeats that act as
limits for excision and integration by transposase
Transposase are frequently encoded by the
transposons
Cut and paste
May be imperfect and leave behind partial sequences
c. Most TEs are transposition inactive as mutations have silenced the
mechanism
i. May still be transcribed by promoters within itself
ii. Becomes transcriptionally active in response to stress

DNA damage
Radiation
Reactive oxygen species
UV radiation
Temperature
Wounds
Infections
iii. Expressions are affected by histone modifications too
In rats, during stress, H3K9me3 levels rise, while
expression of certain TEs decrease
iv. Can have numerous regulatory effects
Sense/ antisense transcriptional activation
Induction of heterochromatic silencing
Small RNA targeting
Alternative splicing
d. Active, mobile TEs can be highly mutagenic and cause genomic
instability
i. Movement activity is supressed by cellular RNAi machinery
ii. Targeted dsRNA is processed by Dicer enzymes to produce
short endogenous small interfering RNAs (esiRNAs), which is
loaded into RNA-induced Silencing Complex (RISC)
RISC binds to chromatin and catalyses formation and
spreading of silencing heterochromatin, repressing
transcription
Recruits heterochromatin proteins and histone
methyltransferase
RISC also recognises and hydrolyses target RNA
transcripts
Post-transcriptional silencing