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

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

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4444

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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

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2

1

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1

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1

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2

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1

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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