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Epigenetics - from mechanisms to odds ratios

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Sage Arbor

on 18 November 2016

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Transcript of Epigenetics - from mechanisms to odds ratios

Epigenetics
From Mechanisms to Odd Ratios
Caloric
Restriction

Sleep
Trauma / Nurturing
Exercise
Inflammation
Barres, R., Kirchner, H., Rasmussen, M., Yan, J., Kantor, F.R., Krook, A., Näslund, E., and Zierath, J.R. (2013). Weight Loss after Gastric Bypass Surgery in Human Obesity Remodels Promoter Methylation. Cell Reports 3, 1020–1027.
Frier, B.C., Jacobs, R.L., and Wright, D.C. (2011). Interactions between the consumption of a high-fat diet and fasting in the regulation of fatty acid oxidation enzyme gene expression: an evaluation of potential mechanisms. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology 300, R212–R221.
↑PPAR-g
↓inflammation
↓lipids in plasma

High fat diet
Fasting
↑ Fatty acid oxidation
Obesity
or

Prader-Willi Angelman
Syndrome vs Syndrome
Dutch Famine
1944
Fragile X
Sporadic cancers:
failed DNA repair
Mechanism's
Histone methylation & acetylation
Cytosine
methylation
= OFF
Grandparents
Parents
Children








4x diabetes
trimester:
mother →
1
2
3
child →
grandchild →
OK
OK
SGA
SGA
OK
SGA
Breast
Cancer
Colorectal
Cancer
BRCA1
HYPERmethylation
MGMT
Angelman
Syndrome

vs

Prader-Willi
Syndrome
Fragile X
HAT &
HDACs
13%
40-90%
Epigenetic
longevity

millions yrs
100's yrs
<1yr
DNMT=DNA Methyl Transferase
SAM = S-adenosylmethionine
SAH = S-adenosylhomocysteine
* = epigenetic activity in vivo
↓melatonin
• 38/200 pregnant women = PTSD
• ↑ cotisol (mom & child)
• 16 genes expressed differently
• 3rd trimester worst
... mass HYPOmethylation
Company
Progenity = only catches large DNA deletions
Natera = a company that can catch epigenetics
Fetal DNA testing
CLOCK = is a HAT
SIRT1 = is an HDAC
URL to this prezi → http://bit.ly/epigenetics-ArborPrezi
Online notes → http://bit.ly/epigenetics-ArborNotes

Sage Arbor
sarbor@marian.edu
http://www.marian.edu/sage
Marian University COM - 2016


GRAPES - more data
much
more

caffeine
A1R
A2R
adenosine Receptors
epigenetic modification of circadian clock
stimultory effect
* Burke, T.M., Markwald, R.R., McHill, A.W., Chinoy, E.D., Snider, J.A., Bessman, S.C., Jung, C.M., O’Neill, J.S., and Wright, K.P. (2015). Effects of caffeine on the human circadian clock in vivo and in vitro. Science Translational Medicine 7, 305ra146–ra305ra146.
* http://www.howsleepworks.com/how_circadian.html
double espresso 3hrs pre sleep
40min delay melatonin/sleep
"hormone of darkness"
3hrs bright light before sleep
85min delay melatonin/sleep
light @ nigiht + caffeine
circadian clock slipped later: delayed sleep next night?
caffeine in early morning advances circadian clock
16 hr fast, followed by big breakfast resets circadian clock
inhibits
Fragile X syndrome is most commonly caused by a CGG trinucleotide repeat expansion in the 5’ region of the FMR1 gene.
Unaffected individuals have 6-50 CGG repeats.
>200 CGG repeats is seen in individuals with fragile X.
↑ hypermethylation at CpG dinucleotides
silencing of the FMR1 gene.


Blue = ♀ = maternal imprinting (♀expressed).
Gray = ♂ = paternal imprinting (♂expressed).
Blue/Gray = ♂/♀ = mixed region of imprinting.
Overkalix study
born :1890, 1905, 1920
Slow Growth Period (SGP) = 8-10♀, 9-12♂
diabetes
http://www.nytimes.com/2014/01/21/science/seeing-x-chromosomes-in-a-new-light.html?_r=0
cornea
skin
cartilage
inner ear
X-Chromosome
Epigenetic
Drugs
Vorinostat (Zolinza 2006)
• approved by FDA for cutaneous T cell lymphoma in 2006.
• HDAC inhibitor.
• ↑ acetylation = ↑gene expression.
• ~30% effective

Many epigenetic therapies have proven
synergistic effects with chemotherapy/irradiation
• Vorinostat plus cytarabine and idarubicin.
• 85% remission rate after initial treatment.
Fraga, M.F., Ballestar, E., Paz, M.F., Ropero, S., Setien, F., Ballestar, M.L., Heine-Suñer, D., Cigudosa, J.C., Urioste, M., Benitez, J., et al. (2005). Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102, 10604–10609.
yellow = same
red & green = diff
http://www.vertex42.com/ExcelTemplates/bmi-chart.html
4/9
Aiken, C.E., and Ozanne, S.E. (2014). Transgenerational developmental programming. Hum. Reprod. Update 20, 63–75.
Vickers, M.H. (2014). Early Life Nutrition, Epigenetics and Programming of Later Life Disease. Nutrients 6, 2165–2178.
Epigenetics good vs bad
Folic Acid
DHF
THF
5-methyl THF
Methionine

Synthase
EtOH
DHFR
5,10 Methylene THF
MTHFR
EtoH prevents Methyl group getting added to DNA,
leads to global hypomethylation
CH3
CH3
Homo
cysteine
Methionine
CH3
CH3
CH3
ATP
SAM
DNA-CH3
DNA
CH3
CH3
CH3
CH3
(S-adenosylmethionine )
SAH
(S-adenosylhomocysteine)
DNMTS
DNA methyltransferases
CH3
de Cabo, R., Carmona-Gutierrez, D., Bernier, M., Hall, M.N., and Madeo, F. (2014). The search for anti-aging interventions: From elixirs to fasting regimens. Cell 157, 1515–1526.
EtOH
x500
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938757/
Stress = chromatin remodeling
↓histone acetylation at BDNF gene in the hippocampus.
Imipramine treatment (Trofanil) (Tricyclic antidepressant)
reversed this process by histone acetylation
Moral: If good parenting doesn’t help; try meds.
• 6 markers changed with age
• 4 hypomethylation
• 2 hypermethylation

Tai Chi slowed age-related methylation changes for all 6
• 5-70% slowing
Ren, H., Collins, V., Clarke, S.J., Han, J.-S., Lam, P., Clay, F., Williamson, L.M., and Andy Choo, K.H. (2012). Epigenetic Changes in Response to Tai Chi Practice: A Pilot Investigation of DNA Methylation Marks. Evid Based Complement Alternat Med 2012.
Glucocorticoid Receptor (GCR , NR3C1) - binds cortisol
HPA
axis
F0
F1
LLG
LLG = Low Licking and Grooming mouse
HLG = High Licking and Grooming mouse
↓GCR
↑GCR
HLG
↑GCR
↓GCR
cross
foster
cross
foster
HDAC inhibitor administered +DNA demtylation
↓Serotonin Receptors due to removal from mother (3 generations)
F0
F1
Booij, L., Wang, D., Lévesque, M.L., Tremblay, R.E., and Szyf, M. (2013). Looking beyond the DNA sequence: the relevance of DNA methylation processes for the stress–diathesis model of depression. Philos Trans R Soc Lond B Biol Sci 368.
Franklin, T.B., Linder, N., Russig, H., Thöny, B., and Mansuy, I.M. (2011). Influence of Early Stress on Social Abilities and Serotonergic Functions across Generations in Mice. PLoS One 6.
removed from mother
↓serotonin response
F2
↓serotonin response
F3
↓serotonin response
Fear conditioning
↓BDNF
via ↑DNA methylation in the promoter region
BDNF (brain derived neurotrophic factor) gene promoter region in hippocampal neurons of rat brains.
Social deprivation 1week of life
•↑ acetylation of the BDNF gene histones
cocaine
↑BDNF
Mood disorders epigenetic treatment
Tsankova N, Berton O, Rentha W, Kumar A, Neve R, Nestler E. (2006). Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature and Neuroscience. 9(4):519
Suicide
Abused children predisposed to suicide (Meany 2009)
McGowan, P. O. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12, 342–348 (2009).
Early abuse ↓GCR (NR3c1)
Relative Hippocampal NR3C1 expression levels


Abused Children
Not abused Children
http://californiaagriculture.ucanr.edu/landingpage.cfm?article=ca.v060n03p132&fulltext=yes
P E O P L E T H A T C O M M I T S U I C I D E
If a male with Angelman syndrome had children with a healthy female, what would his offspring have?
AS , PWS, either, neither?







Prader-Willi or healthy depending on which chromosome from the father the child got.

Uniparental disomy - can cause 2 diseases without any deletions






20-30 million reads !!!
resveratrol
lycopene
http://www.anti-agingfirewalls.com/2011/11/08/latest-p16ink4a-senescence-reversing-research-%E2%80%93-an-important-but-not-game-changing-contribution/
https://www.fightaging.org/archives/2011/04/p16-and-the-balance-between-cancer-and-aging.php
Notable - maternal and paternal imprints
NOT ERASED in first wave
ERASED in second wave
just for primordial germ cells (PGCs) that become egg and sperm
these are reporgrammed as paternal and maternal based on sex of offspring
http://ghr.nlm.nih.gov/condition/angelman-syndrome
http://ghr.nlm.nih.gov/condition/prader-willi-syndrome
http://ghr.nlm.nih.gov/condition/fragile-x-syndrome
http://learn.genetics.utah.edu/content/epigenetics/imprinting/
Objectives
Provide a working definition of epigenetics and contrast an epigenetic change with a mutation.
Contrast the normal process of genomic imprinting with abnormal changes in epigenetic tags seen in several diseases described.
Describe how imprinting influences the expression of Angelman and Prader-Willi syndromes.
Describe evidence that nutritional status can influence the epigenetic profile of later generations.
Describe the mechanism of action of Vorinostat.
Describe the mechanisms (protein interaction or transcription) and effect on protein expression (up or down) of the epigenetic tags involving cytosine methylation (CpG islands); histone acetylation; and non-coding RNAs.
Describe the longevity, erasure, and reprogramming of DNA methylation epigenetic marks.
Describe the epigenetic effects of exercise and to what degree they affect breast cancer.
Describe the protective effect of sleep and harm of disrupted circadian in relation to cancers discussed.
Diagram the epigenetic effect of alcohol involving folic acid; SAM; SAH; ROS; sirtuin; and methylated DNA and contrast caloric restrictions effect on Sirt1.
Describe prototypical epigenetic changes seen in early and late cancer.
Diagram the circadian interactions between folate, NAD+, Sirtuins (SIRT), BMAL, CLOCK, CRY, and PER proteins.
Diagram axins interaction and epigenetic effects involving the wnt signalling pathway.
Be able to explain disruptions in attachment and risk of adult suicide due to behavioral epigenetics; the HPA axis and glucocorticoid receptors  (NR3C1).
Be able to  cite one animal or human study  linking psychological trauma to epigenetic changes that create problems in self calming, depression, and anxiety.
Be able to describe the main differences in sleep between older and younger adults and their implication for the well-being of the elderly.
Be able to describe how aging affects melatonin.
...
How do psychotropic medications affect sleep architecture?
Be able to describe 5 ways of helping patients cope with insomnia and fragmented sleep.
Compare pros and cons (cost, resolution, defects) in measuring methylated DNA epigenetics via bisulfite sequencing; restriction digestion; or methylation immunoprecipitation.


↓IGF2 methylation
6 decades later !!!!
Heijmans, B.T., Tobi, E.W., Stein, A.D., Putter, H., Blauw, G.J., Susser, E.S., Slagboom, P.E., and Lumey, L.H. (2008). Persistent epigenetic differences associated with prenatal exposure to famine in humans. PNAS 105, 17046–17049.
Roseboom, T.J., Painter, R.C., van Abeelen, A.F.M., Veenendaal, M.V.E., and de Rooij, S.R. (2011). Hungry in the womb: what are the consequences? Lessons from the Dutch famine. Maturitas 70, 141–145.
"thrifty pheotype"

good →bad
calorie supply
♀→♂→♀
↓GSH
↑ROS
(↑oxidative stress)
methionine adenosyl transferase
(MAT)

MAT
Mandrekar, P. (2011). Epigenetic regulation in alcoholic liver disease. World J Gastroenterol 17, 2456–2464.
EtOH epigenetic recap →
http://pubs.niaaa.nih.gov/publications/arcr351/6-16.htm
▲histone acetylation
EtOH metabolism causes : ↓NAD+, ↓Sirt1, ↑ROS
H3K9
Alcohol Dehydrogenase
global
hypomethylation
Glutathione
miRNAs
MT-R1
Adenylyl Cyclase
MT-R2
↑PKC
E-box
RORE
CLOCK = is a HAT
SIRT1 = is an HDAC
Food
Cry
Per
Cry
Per
P
Cry
Per
BMAL1
CLOCK
RevErbα
RORα
,
RevErbα
RORα
NAMPT
NAMPT
Cry1/2
Per1/2
,
,
,
BMAL1
Aging
NAD+ Salvage pathway
NAD+
Sirt1
PGC-1α
NAD+
↑ CLOCK
↑ BMAL1
↑ NAMPT
↑ PGC-1α
↑ SIRT1
↑ PER
↑ Rev-Erbα
↑ RORα
↑ Cry
Cry
Per
P
P
Cry
Per
P
Ubq
Ubq
Ubq
Ubq
Ubq
Ubq
Reg 10% proteins
↑ Melatonin
Tryptophan is starting material for NAD+, unrelatedly the salvage pathway for NAD+ is controlled by CLOCK genes which are controlled by melatonin.
Melatonin is similar to serotonin so can interact with the serotonin receptor. Patients taking SSRIs can have effects on their melatonin due to blocking of the channel.
Ramsey, K.M., Yoshino, J., Brace, C.S., Abrassart, D., Kobayashi, Y., Marcheva, B., Hong, H.-K., Chong, J.L., Buhr, E.D., Lee, C., et al. (2009). Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis. Science 324, 651–654.
↓melatonin
"hormone of darkness"
miRNAs
Acetyl
http://www.crsociety.org/
Mice fed 2/3rds less,
live 2/3rds longer !!!
35 → 55 months
Weindruch R, et al. (1986). "The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake." Journal of Nutrition, April, 116(4), pages 641-54.
Is the BMI outdated? Olypmic weighlifters are obese? Newer methods below
• Surface-Based Body Shape Index (BMI + ~surface)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692532/
http://jech.bmj.com/content/70/1/90.long
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399847/
http://absi-calc.appspot.com/
• Body Shape Index (BMI+waist)
Lit→
Lit→
Calculator→

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399847/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544789/



Paternal/Maternal impriting survives 1st wave of reprogramming
(small fraction of genome methylation)
Paternal/Maternal impriting reset in 2nd wave of reprogramming
Weiskirchen, S., and Weiskirchen, R. (2016). Resveratrol: How Much Wine Do You Have to Drink to Stay Healthy? Adv Nutr 7, 706–718.
melatonin
supplements
delayed sleep-wake phase syndrome
(a circadian sleep-wake rhythm disorder)

low melatonin levels
Ketamine
1.Bellet, M. M., Vawter, M. P., Bunney, B. G., Bunney, W. E. & Sassone-Corsi, P. Ketamine Influences CLOCK:BMAL1 Function Leading to Altered Circadian Gene Expression. PLOS ONE 6, e23982 (2011).
Ac
Ac
Sirt1
AKT = Protein kinase B
eIF4e = Eukaryotic translation initiation factor 4E
FOXO = Forkhead box protein O1
IR = Insulin Receptor
IRS1 = Insulin Receptor Substrate 1
mTORC1 = Mammilian Target of Rapamycin 1
PGC-1α = peroxisome proliferator-activated receptor-γ coactivator 1α
PTEN = Phosphatase and tensin homolog
PI3K = Phosphatidylinositol 3-kinase
https://en.wikipedia.org/wiki/PI3K/AKT/mTOR_pathway
1.Wang, C. et al. Targeting the mTOR Signaling Network for Alzheimer’s Disease Therapy. Molecular Neurobiology 49, 120–35 (2014).
2.Hands, S. L., Proud, C. G. & Wyttenbach, A. mTOR’s role in ageing: protein synthesis or autophagy? Aging (Albany NY) 1, 586–597 (2009).
3.Masui, K., Cavenee, W. K. & Mischel, P. S. mTORC2 in the center of cancer metabolic reprogramming. Trends in Endocrinology & Metabolism 25, 364–373 (2014).
4.Li, Y. et al. MAF1 Suppresses AKT-mTOR Signaling and Liver Cancer through Activation of PTEN Transcription. Hepatology (2016). doi:10.1002/hep.28507

Sirt1
[activating]
mTORC1
PGC-1α
[activating]
p53
p16
[inhibiting]
[inhibiting]
Cancer →
Insulin
IR
IRS1
PI3K
Tsc1/2
mTORC2
P
4E-BP
EI4Fe
mRNA 5' cap bending
Food
↑ Lifespan
Ac
Ac
Ac
Caloric
Restriction
Exercise
Epigenetic p16 promoter modification
c-Myc
FOXO
Rapamycin /
Rapalogs
Warburg effect
(Glucose → Lactate in cancer)
Protein Synthesis
ClassII Hdacs
Ac
Akt
Autophagy
cell cycle arrest
mitochondria energy metabolism
Rapamycin
GCR
GCR
GCR
Glucocorticoid Receptor
(binds cortisol)
P

(FAST antidepressent)
Full transcript