Epigenomics - Stanford UniversityEpigenomics Michael Snyder February 20, 2018 Slides from: Joe...
Transcript of Epigenomics - Stanford UniversityEpigenomics Michael Snyder February 20, 2018 Slides from: Joe...
Epigenomics
Michael Snyder
February 20, 2018
Slides from: Joe Ecker, Anne Brunet, Joanna Wysocka, Jason Reuter
Disclosures: Personalis, GenapSys, SensOmics, Qbio
Definition: EpigenomicsThe study of the complete set of epigenetic modifications on the genome that can modify DNA instructions, turning on and off genes, or control the production of proteins.
These modifications occur when chemical compounds or proteins bind to DNA and “mark” the genome. They do not alter the sequence itself.
A Symphonic ExampleDNA Phenotype
Image: mooogmonster
Epigenetic changes
Identical twins are not identical
Factors outside our DNA influence of phenotypes and health
Epigenomics: Two Major types
1) DNA methylation
2) Histone modification
The Epigenome – DNA Methylome
Often occurs at CpG
>28 million CpG sites in the
human genome.
Human genome consists of
vast oceans of DNA sequence
containing few but heavily
methylated CpG dinucleotides.
Punctuated by short regions with unmethylated CpGs occurring at
higher density, forming “CpG islands” in the genome, often at gene
promoters.
HydroxyC methylation: associated with gene regulation (not
discussed)
The Human Epigenome
Maleszewska & Kaminska, Cancers, 2013
Methylation in promoters:Gene expression turned off
InactiveActive C
hromatin
Ac: Acetylation
The Human Epigenome
Maleszewska & Kaminska, Cancers, 2013
Methylation in promoters:Gene expression turned off
InactiveActive C
hromatin
Ac: Acetylation
Dnmt: DNA methyltransferase
TET: “Demethylation”
HMT: Histone MethylTransferase
KDM: Histone Demethylase
HAT: Histone AcetylTransferase
HDAC: Histone DeACetylase
Modifying enzymes
How to detect DNA methylation: Bisulfite sequencing
• Sodium bisulfite converts unmethylated Cytosine into UridineConverts to Thymine after PCR ampification
• Does not effect on methylated Cytosine.
www.illumina.com
Whole-genome versus targeted bisulfite sequencing
Lee et al (2013) Cancer Letters
• Whole-genome bisulfite sequencing is very expensive
• WGBS is also inefficient, as about 65% of all 101-bp reads do not even contain any CpGs.
• To detect partial methylation at high sensitivity need a greater sequencing depth.
• à Targeted bisulfite sequencing instead
DNA Methylation Associated with Environmental and Other Factors
• Nutrition• Exercise• Environmental exposure
• Aging• Disease
Much of what we know comes from model organism
Nutrition and DNA MethylationHoney BeesExtensive differential methylation workers and queen
“Royal Jelly”silences Dnmt3 DNA Methyl transferase
You Can Buy This Stuff
Nutrition and DNA Methylation
Agouti Mouse• Paracrine signalling molecule
that affect coat color• Yellow, obese, diabetic
unmethylated• Brown healthy methylated• Transposon
Nutrition and DNA Methylation
BPA exposure
Agouti Mouse• Affected by Nutrition and Environment• Methyl rich diet (SAM, folate) by Mom Suppresses yellow• BPA – (bisphenol A) polycarbonate plastic precursor
DNA Methylation Associated with Many Diseases and Traits
Asthma and Allergies (Nadeau)
Aging
Nutrition
Cancer
Exercise
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44
44
44
4444
444444
44
44444444444444
4444
4444
4444
44
4444
44
44
44
44444444
4444
44 444444
4444
44
4444
44
44 444444
444444
44
4444 444444
444444 4444
44
4444
44
44444444 4444
44
444444444444
4444
44
44
44
444444
44
444444
444444
44
4444
44
444444 444444444444
44
44
4444444444
44
444444
44444444 4444
44
4444
44
44
4444
44
44
444444444444
44
444444444444
4444
44
4444 4444
444444
44444444
44444444
44
44
44
44444444
4444
444444
4444
444444
4444
44
44444444
44
44
44444444444444
444444
44
4444
4444
44
44
44444444
44
44
44
4444
444444444444444444
44
44
44444444
44
4444
4444 44
44
4444
44
4444
44444444
4444
44
4444
44
44
44 44444444
444444
444444
4444
44444444
44
444444
4444
44
444444
44
4444
44
4444
44
4444
44 44
444444
44
4444
44
444444
444444
4444
44444444
444444
4444
4444 444444 44
44
44
44
444444
444444
444444
44
44
444444
44
44
44
44
444444 44
4444
44
4444
44
44
444444
44
44
444444
44
44
44
44
444444
44444444
4444
44
44
44
4444
4444
4444
4444 44
444444
44
444444
444444
44444444
44444444
44444444
44
44
444444
44
4444
44
44 4444 44
44
44
44
44
44
4444
444444
44
44
444444
44
44
44
4444
44
4444
44
4444 44444444
44
44
444444
4444
444444
44
4444444444
4444
44
44
44
44
4444
44444444
4444
44
44
4444
44
44
4444
4444
44
44
4444
44 4444
44
4444
44
44
444444
44444444
444444444444
4444
4444
44
44
44444444
4444
4444444444
4444 4444
4444444444
44 44
44
44
4444
444444 44
44
444444
44
44
44
44
444444
4444
4444
4444
444444
44
44
44
44 4444
4444 44
44
44
44
4444444444 44
44
44 444444
44444444
444444
44
44444444
44
4444
4444
44444444
444444
4444
4444 444444
4444
444444
444444
4444444444
44
44
44
484848484848484848484848484848484848 48 4848484848484848484848484848484848484848484848484848484848 49494949494949494949494949 4949494949494949494949 4949494949494949494949494949494949494949494949494949494949494949494949494949494949494949494949494949494949494949494949495050505050505050505050505050505050505050505050505050505050505050505050505050505050505050505050505050505050
10 20 30 40 50
020
4060
F Brain Cerebellar err=5.9 cor=0.92, p=9.5e−09
m.age(training set CpGs)
Age
5454
54
5454
54
545454
5454
54
54
54 54
5454
5454
54
0 10 20 30 40 50 60
020
4060
G Brain Occipital Cortex err=1.5 cor=0.98, p=3.3e−11
m.age(training set CpGs)
Age
55
55
55
55
55
55
55
55
5555
55
55
55
55
55
55
40 50 60 70 80 90
3050
7090
H Breast NL Adj err=13 cor=0.87, p=2.5e−34
m.age(training set CpGs)
Age
56
56
56 56 5656 56
56
56
56
56
56
56
56565656
56
56
56
56
56
56
56
5656
5656
5656
5656
56
56
56 56
56
56
56 56
56
565656565656 56
56
56
5656
56
56
56
5656
56
56
56
5656
56
56
565656
5656
56
56
56
5656
56
56
56
56
5656
56
575757
575757
5757
57
5757
5757 5757
57
575757
5757
57
57
5757
57 57
0 1 2 3 4
0.0
0.5
1.0
1.5
I Buccal err=0.37 cor=0.83, p=5.1e−14
m.age(training set CpGs)
Age
58
58
58
58
58
58
58
58
58
58
58
58
58
58585858
58
58
58
58
58
58
58
58
58
58
58
58
58 58
58
58
58
58
58
58
5858
58
5858
58
5858
58
58
58
58
58
58
40 50 60 70 80
4060
80
J Colon err=5.6 cor=0.85, p=1.5e−11
m.age(training set CpGs)
Age
59
5959 595959
59
59
59 59
59
59
5959
59
59
5959
59
59
59
59
59
595959
59
5959
595959
59
5959
5959
59
65 70 75
7375
77
K Fat Adip err=2.7 cor=0.65, p=0.042
m.age(training set CpGs)
Age
60 6060 60
6060
6060
6060
46 48 50 52 54
5560
6570
L Heart err=12 cor=0.77, p=0.073
m.age(training set CpGs)
Age
61
61
61
61
61
61
20 40 60 80
4060
80
M Kidney err=4.6 cor=0.86, p=3.6e−59
m.age(training set CpGs)
Age
62
62
6262 62
6262
6262 6262 6262
6262
62
62
6262
6262
6262
62
6262
62
62
62
62
6262
62 62
62 62
62
6262
62626262
626262
62 6262 6262
62
62
62
62 6262626262
62
62 62
6262
62
62 62
6262
62
6262
62
62
6262
62
62
62
6262
6262
62
62
62
62
6262
62
6262
62
62
62 62
626262
62 626262
62
62
626262
62 62
6262
62
62
62
626262
62
626262
62
6262
62
62
6262
62
62
62
6262
6262
6262
62
6262
62
6262
62
62
62
62 62
62
626262
62
62
626262 62
6262
6262
62
62
62
626262
62
62
62
62
62
62
62
626262
62
62
6262
62
62
62
6262
62 62
6262
626262
62
62
20 30 40 50 60 70 80
2040
6080
N Liver err=6.7 cor=0.89, p=1.7e−13
m.age(training set CpGs)
Age
6363
6363
63
6363
63
63
63
63
63
63
63
6363
63
636363
63
63
63
63
63
63
63 636363 63
63
6363
63
63
63
40 50 60 70 80
5070
O Lung NL Adj err=5.2 cor=0.87, p=7.8e−09
m.age(training set CpGs)
Age 64
64
64 64
64
64
64
646464 64
64
64
64
646464
64
64
64
64
64 64
64
64
64
35 40 45 50 55 60 65
3050
70
P Muscle err=18 cor=0.7, p=6.1e−11
m.age(training set CpGs)
Age
656565 65656565 656565
6565
65 65 65656565 65656565
66666666 6666666666 66 666666 6666666666 666666 66666666 66666666666666666666 6666 66 6666 66 666666
20 30 40 50
2030
4050
Q Saliva err=2.7 cor=0.83, p=2.8e−14
m.age(training set CpGs)
Age
68 6868
68
6868 68
68
68 68
6868
68
68
68
6868
6868
68
68
68
6868
68
68
686868
6868
6868
686868
68
6868
686868 68
68
68
68
68 6868 686868
20 30 40 50
2030
4050
R Uterine Cervix err=6.2 cor=0.75, p=1e−28
m.age(training set CpGs)
Age
696969
69
6969
69
69
69
6969 6969
6969 6969 6969
69 69
6969 69
69696969
69
69
69
69
69
696969
6969
69
6969
69
69
696969 6969 69
6969 69
69
696969
69
696969
69
69 6969
6969
6969
69
6969
69 6969
6969
69
6969
69
696969
69
69
6969
69 6969 69
69
69696969
69
69
6969
69
69
6969
6969
69
69
69
6969
69
696969
69
69
6969
696969
696969
69
6969
69 69696969
69
6969
6969
696969 696969
69
69
69 6969
696969
40 50 60 70 80
4060
80
S Uterine Endomet err=11 cor=0.55, p=0.0024
m.age(training set CpGs)
Age
7070
7070
7070
70
7070 70
70
70
70
70 70
70707070 70
70
70
70
707070 7070
25 30 35 40 45 50 55
2030
4050
60
T B cells from progeria err=4.4 cor=0.46, p=0.073
m.age(training set CpGs)
Age
B.EBVB.EBV
B.EBV
B.EBV
B.EBV
B.EBV B.EBV
PBMCPBMCPBMCB.EBVB.EBV
B.EBV
B.naiveB.naive
B.naive
Horvath Genome Biology 2013 14:R115 doi:10.1186/gb-2013-14-10-r115
DNA Methylation Correlates With Age
Measure Methylation at 353 CpG Sites “Clock CpGs”
Correlates Well with Age Across Many Tissues
Advanced Aging in AIDs Patients
Nelson et al. AIDS. 2017 Feb 20;31(4):571-575. doi: 10.1097/QAD.0000000000001360.Identification of HIV infection-related DNA methylation sites and advanced epigenetic aging in HIV-positive, treatment-naive U.S. veterans.
19 HIV+ and 19HIV- PBMCs; ~9 yr follow up
Human DNA methylation at putative MEs is influenced by season of conception in the Gambia
Waterland et al., PLoSGenet 2010
Gambia –rainy season: hungry, dry season: lots of food
DNA from peripheral blood leukocytes
Human DNA methylation at putative MEs is influenced by season of conception in
the Gambia
Silver et al. Genome Biol. 2015 Jun 11;16:118. doi: 10.1186/s13059-015-0660-y
VTRNA2-1 gene is affected
- Affects immune system & Tumor suppressor
DNA from peripheral blood leukocytes
Exercise and DNA Methylation
Lindholm et al. Epigenetics. 2014 Dec 2;9(12):1557-69. doi: 10.4161/15592294.2014.982445.
• Many studies have linked exercise and DNA methylation differences are specific genes
Recent study Lindholm et al
23 people. Bike use one leg 4X/Week 45’ for 3 months; other leg is control
Measure gene expression and DNA methylation (arrays) beginning and end of training on each leg (muscle biopsy)
4919 sites differed in trained leg (5% FDR)
Aging (Albany NY). 2017 Feb 14. doi: 10.18632/aging.101168. [Epub ahead of print]
Epigenetic clock analysis of diet, exercise, education, and lifestyle factors.Quach A1, Levine ME1, Tanaka T2, Lu AT1, Chen BH2, Ferrucci L2, Ritz B3,4, Bandinelli S5, Neuhouser ML6, Beasley
JM7, Snetselaar L8, Wallace RB8, Tsao PS9,10, Absher D11, Assimes TL9, Stewart JD12, Li Y13,14, Hou L15,16,
Baccarelli AA17, Whitsel EA12,18, Horvath S1,19.
Author information
AbstractBehavioral and lifestyle factors have been shown to relate to a number of health-related outcomes, yet there is a need for
studies that examine their relationship to molecular aging rates. Toward this end, we use recent epigenetic biomarkers of
age that have previously been shown to predict all-cause mortality, chronic conditions, and age-related functional decline.
We analyze cross-sectional data from 4,173 postmenopausal female participants from the Women's Health Initiative, as
well as 402 male and female participants from the Italian cohort study, Invecchiare nel Chianti.Extrinsic epigenetic age
acceleration (EEAA) exhibits significant associations with fish intake (p=0.02), moderate alcohol consumption (p=0.01),
education (p=3x10-5), BMI (p=0.01), and blood carotenoid levels (p=1x10-5)-an indicator of fruit and vegetable
consumption, whereas intrinsic epigenetic age acceleration (IEAA) is associated with poultry intake (p=0.03) and BMI
(p=0.05). Both EEAA and IEAA were also found to relate to indicators of metabolic syndrome, which appear to mediate
their associations with BMI. Metformin-the first-line medication for the treatment of type 2 diabetes-does not delay
epigenetic aging in this observational study. Finally, longitudinal data suggests that an increase in BMI is associated with
increase in both EEAA and IEAA.Overall, the epigenetic age analysis of blood confirms the conventional wisdom regarding
the benefits of eating a high plant diet with lean meats, moderate alcohol consumption, physical activity, and education, as
well as the health risks of obesity and metabolic syndrome.
Epigenetic Age and Other Lifestyle Factors
912
Adenovirus Infection
694679 683 688 700680
711 735
796 840
Adenovirus Infection
944 948 984945 959 966
HRV Infection
1030 10381029 1032 1045 1051 1060
400186185
255
116
369
380
329322
Day from 1st HRV
Infection (D)
RSV Infection
297 301289 292 294 307 311290
HRV Infection
4 210
476 546532
HRV Infection
625615 618 620 630616
602 647-123
Day from 1st HRV
Infection (D)
14151453
1487
15161526
HRV Infection
1714
1720 17431716 1723 1729
Infection
19081906
11091124 1164 12001227128413161319 13231331133813601381153
6
156
4
158
9
161
2
162
8
163
1
164
3
168
0
169
5
170
2
170
9
1
7
5
0
1
7
5
7
1
7
6
4
1
7
7
1
1
7
7
4
1
7
7
9
1
7
9
2
1
8
1
5
1
8
2
8
1
8
3
5
1
8
4
2
1
8
4
9
1
8
5
2
1
8
5
9
1
8
7
1
1
8
9
4
Personal Omics Profile94 months; >250 Timepoints; 11 Viral Infections
Chen et al., Cell 2012, unpublished
Skin Rash
HRV
Exercise
RSVSkinRash/Itch
HRV
AdenovirusHRVHRV
Changed life style
}
Norm
al Range 3.8-5.7%
{
Nor
mal
Ran
ge 7
0-99
mg/
dL
Extended Time Line
26Longitudinal Personal DNA Methylome Reveals Epigenomic Signatures of a Chronic Condition
Transcriptome Changes Many Times Especially at Viral Infections
Methylome Changes Twice: At Glucose Misregulation Times
Glucose Homeostasis
Father
Mother
T à CInactivated by
mutation
Inactivated by DNA
MethylationM MMMethylated CpGs
Few (3/47 reads) RNAs
Lots of RNAPDE4 DIP Gene
Gene Inactivation by Mutation and Methylation: PDE4 involved in eosinophilia
electron micrograph of chromatin
nucleosome
DNA
histonesK. Luger
Epigenetics and Chromatin
Chromatin undergoes reversible chemical modifications, which have regulatory properties
Two Common Epigenetics MarksLysine Acetylation and Methylation
K KacKme
+14 Da +42Da
b-hydroxybutyrylation CoA
b-Hydroxybutyryl-CoA
b-Hydroxybutyryllysine
Mol Cell, 2016, 62:194-206.Mol Cell, 2016, 62:169-80. Mol Cell, 2015, 58: 1-13. Cell, 2014, 159(2): 458. Cell Metabolism, 2014, 19: 605-17.Nature Chem Biol. 2014, 10: 365-370. Mol Cell, 2013. 50: 919-30. Cell, 2011. 146:1016-28. Nature Chem Biol. 2011. 7: 58-63.Mol Cell Proteomics 2011. M111.012658. Mol Cell Proteomics. 2009, 8:45-52. J Proteome Res. 2009, 8:900-6. Mol Cell Proteomics. 2007. 6:812-9.
~350 New Histone Marks Me
Ac
Bu
Fo
OH
Ma
Su
Pr
Cr
Hib
Bhb
Methylation
Acetylation
Butyrylation
Formylation
Hydroxylation
Malonylation
Succinylation
Propionylation
Crotonylation
2-Hydroxyisobutylation
b-hydroxubutyrylation
SuCrHib
MeHib
SuCrHib
SuCrHib
SuCrHibHib HibHib
SuHib
SuHib Hib
FoHib
MeSuCrHib
HibHibSuHib
MeHib
HibMeHib
CrHib
CrHib
Hib Ph
NH2-S1··VKKK22AAK25K26··K33ASGPPV··K45··K51ERSG··K62K63··Y70··K74··K80··K84··K89··K96··GSFK105·· K212··K167··K158··K147PT145··AKKPKK135··K128PKTG··K120··
K116··K109KN··
OHSu
NH2-SGRGK5QGGK9ARAKAK··LRK36GNY39··R42··LELAGNAARDNK74K75··R88··K95··VLLPK118K1
19T120ES122··K125··
BuHibbhb
MeSuHibbhb
SuCrHibbhb
Hib Hib
MeCrHibbhb
Crbhb
MePrCrbhbOH Ph
BuSuPrHibbhb PhMe Me
NH2-PEPAK5··K11K12GSK15K16AVTK20AQK23K24··KRSRK34ESY37··K43··K46··DTGISSK57··ASR79··Y83NK85RS··K108··K116AVTK120··
BuSuCrHibbhb
BuCrbhb
MeBuCrHib
BuCr
BuCrbhb
MeBuCrHibbhb
BuSuHib
SuHibbhb
MeFoMaSuHibbhb
FoSuHibbhb
BuCrHib Hi
b
SuCrHibbhb
SuHib
MeHib OHO
H
MeSuHibbhbMe
FoMaSuPrHibbhb
NH2-ARTK4QTARK9STGGK14QPRK18ALATK23AARK27SAPATGGVK36KPH··VALREIRRYQK56··LLIR63K64··K7
9··K115RVTIMPK122
CrHibbhb
BuCrHibbhb
BuSuHibbhb
BuSuCrHibbhb
BuSuPrCrHibbhb
CrHib
AcBuSuHibbhbHib
BuSuHibbhb Bu
BuSuHibbhb Me
NH2-SGRGK5GGK8GLGK12GGAK16RHRKVLRDNIQGITK31··R35RLARRGGVK44RISGLIY51EETR55GVLK59VFLENVIR6
7··K77RK79··Y88ALK91··
BuPrCrHib
BuPrCrHibbhb
BuSuPrCrHibbhb
BuSuPrHib
MeBuPrCrHib
BuSuPrHib
BuSuPrHibbhb
BuPrHib
MeHib
MeBuSuPrHibbhbOH OHMe Me Me
H1.2
H2A
H2B
H3
H4
Additional chromatin modifications
Covalent modifications of histone proteins
acetylation lysinemethylation
argininemethylation
phosphor-ylation
Me
K MeMeKAc
RMeMe
S/TP Ub
KSumo
K
ubiquitin-ylation
sumo-ylation
Non-covalent mechanisms: ATP-dependent chromatin remodeling
Writers, readers and erasers of histone modifications
writer eraser reader
acetylation
methylation
acetyltransferases deacetylases
methyltransferases demethylases
kinases phosphatasesphosphoryl.
bromodomains
chromodomains,PHD fingers, MBT
14-3-3, BRCT
MODIFICATION:
From J. Wysoka
37
Histone Marks Representing a Variety of Functional Elements
Active Genes
Repressed Genes
Chromatin variation across individuals
SAN
CEU
YRI
Asian
Enhancer related marksare more variable than RNA
Kasowski et al 2013 Science
Epigenetics and Cancer
Cancer is a genetic disease
Cancer is also an epigenetic disease
Epigenetics and Cancer
1. Many epigenetic modifiers are mutated in cancer
2. Both global patterns and key targets are altered in methylation in cancer
3. Methylation patterns can guide therapeutics
4. Methylation can guide diagnostics and ?perhaps prognostics?
Epigenetic modifiers are frequent targets for mutation in cancer
Recent sequencing studies show that mutations in the classes of epigenetic modifiers are frequently observed in various types of cancers, highlighting the crosstalk between genetics and epigenetics:
- DNMT3A mutations in AML (next slide)
- IDH1/2 mutations in glioblastoma
- EZH2 mutations in breast, colon, pancreas, melanoma,…
You & Jones, Cancer Cell, 2012
DNMT3A mutations in leukemiaMutations in DNMT3A, an enzyme involved in de novo methylation of CpGs, are among the most common somatic mutations, occurring in 25% of acute myeloid leukemia (AML).
DNMT3A mutations have also been found in myelodysplastic syndromes (MDS).
Indicates that aberrant epigenetic modulation of the genome has a pathological role in leukemogenesis.
Location of mutations in DNMT3A in AML
More Examples
Black: DNA MethylationRed: Chromatin Modification
http://www.tumorportal.org/figure/2
The methylome and major changes that occur in cancer
The cancer methylome is characterized by widespread Hypo-methylation & focal CpG-island Hyper-methylation, often in promoters of tumor suppressor genes.
Stirzaker et al., Trends in Genetics, 2014
Methylation-based classification of colorectal cancer correlates with cancer
gene mutation status
Hinoue, T et al. (2012). Genome research, 22(2), 271–82
BRCA DNA Methylation and Mutation in Ovarian Cancer
Genes can be inactivated by either Mutation or DNA Methylation
APC FANCE PMS2
ATM FANCF PRSS1
BLM FANCG PTCH1
BMPR1A FANCI PTEN
BRCA1 FANCL RAD51C
BRCA2 LIG4 RET
BRIP1 MEN1 SLX4
CDH1 MET SMAD4
CDK4 MLH1 SPINK1
CDKN2A MLH2 STK11
EPCAM MSH6 TP53
FANCA MUTYH VHL
FANCB NBN
FANCC PALB2
FANCD2 PALLDFrom Jim Ford
Unexplainedfamilial risk
BRCA1
BRCA2
Other known
Familial Breast Cancer: Most Is Unexplained
Cancer Genome-Epigenome Interaction: Gene body methylation contributes to cancer-causing mutations
• Methylation of cytosine strongly increases the rate of C→T transition mutations.
• Due to “spontaneous deamination” of cytosine, which forms thymine.
• In somatic cells, gene body methylation is a major cause of cancer gene mutations in tumor suppressor genes, such as TP53.
The epigenome as a therapeutic target
Abnormal hyper-methylation often silences the expression of tumor suppressor genes. Drugs, such as Dacogen and Vidaza (5-azacytidine), may reverse tumor-associated gene silencing through their ability to disrupt DNA methylation.
Hamm and Costa, Pharmacology & Therapeutics, 2015
The histone deacetylase inhibitors Zolinza and Istodax may reverse tumor-associated gene silencing through their ability to disrupt aberrant posttranslational histone alterations. (Subcutanteous T-cell lymphoma; CTCL)
The reversible nature of epigenetic modifications provides an exciting opportunity for the development of therapeutics.
Links Between DNA Methylation and Vitamin C
Stem cells treated with physiological Vitamin C demethylate their enhancers
TET mutations occur in leukemias and other cancers
Cancer patients often have low levels of Vitamin CIn mice Vitamin C helps reduce tumors.
Vitamin C (ascorbic acid) is a cofactor for TET (as well as many other enzymes)
Methylation of certain genes can influence sensitivity to chemotherapeutic drugs
Toyota et al., Cancer Science,
2009
Best known example for promoter methylation influencing treatment: MGMT
• The O(6)-methylguanine-DNA methyltransferase (MGMT) encodes a DNA repair enzyme that can abrogate the effects of alkylating chemotherapy such as temozolamide.
• Alkylating chemotherapy damages DNA and kills tumor cells.
• However, if the MGMT gene is active (unmethylated promoter), the damage is rapidly repaired.
• Malignant gliomas may have the MGMT gene inactivated due to methylation of its promoter region.
• Thus, in gliomas, MGMT promoter methylation is a favorable prognostic marker in the setting of either radiation or chemotherapy.
DNA methylation of specific marker genes can be used as a biomarker for cancer detection and diagnosis
Summers et al., Journal of Cancer, 2013 http://www.epiprocolon.com
Conclusions
1. Epigenomic regulation is widespread
2. Occurs by multiple mechanisms
3. Is involved in many important biological processesCancer, Aging, Nutrition
4. Cancer: Potentially for biomarkers for prognostics and diagnostics