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Environmental Epigenomics in Health and Disease pp 127–160Cite as

The Intersection of Genetics and Epigenetics: Reactivation of Mammalian LINE-1 Retrotransposons by Environmental Injury

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Part of the book series: Epigenetics and Human Health ((EHH))

Abstract

Transposable elements such as LINE-1 (long interspersed nuclear element-1 or L1) are mobile genetic moieties within the genome. L1 retrotransposons comprise 21 % of the human genome by mass, and up to 100 are believed to remain retrotransposition competent within the human genome. During embryonic development, the genome undergoes reprogramming events defined by specific patterns of DNA methylation established de novo after implantation and preferentially targeted to repetitive sequences. Recent studies in the Ramos laboratory have shown that the ability of polycyclic aromatic hydrocarbon carcinogens, such as benzo(a)pyrene, to reactivate L1 transcription and retrotransposition in mammalian cells involves dysregulation of epigenetic programming mediated in part via mechanisms involving the aryl hydrocarbon receptor, a ligand-activated transcription factor and regulator of several other biological processes. The most detrimental effect of L1 on the genome is believed to be insertion into functional sequences that severely compromise gene function. Other studies have shown that L1 reactivation mediates changes in genetic programming of differentiation networks. Because L1 insertions can have a profound impact on primary genetic structure as well as epigenetic status of the host, they represent ideal molecular targets for development of novel epigenetic therapies targeting medical conditions that involve derangements of L1 activity.

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Abbreviations

3′ UTR:

3′ Untranslated region

5′ UTR:

5′ Untranslated region

α NP or ANF:

α-Naphthoflavone

Ac:

Activator

AHR:

Aryl hydrocarbon receptor

AIDS:

Acquired immune deficiency syndrome

AML:

Acute myeloid leukemia

AP-1:

Activator protein-1

APL:

Acute promyelocytic leukemia

AR:

Androgen receptor

ARE/EpRE:

Antioxidant/electrophile response element

ARNT:

Aryl hydrocarbon receptor nuclear translocator protein

ATM:

Ataxia telangiectasia mutated

AZT:

Azidothymidine

BaP:

Benzo(a)pyrene

bHLH:

Basic helix-loop-helix

c-myc:

Myelocytomatosis viral oncogene homolog (avian)

C/EBP:

CCAAT/enhancer-binding protein

CpG:

5′ Cytosine-phospho-guanine

CREB:

Cyclic AMP-responsive element binding protein 1

Ds:

Dissociator

DNMT:

DNA methyltransferase

ERα:

Estrogen receptor α

ETO:

Eight-twenty-one

GFP:

Green fluorescent protein

H2BK:

Histone H2B lysine residue

H3K:

Histone H3 lysine residue

HAT:

Histone acetylase

HATi:

Histone acetylase inhibitor

HCG or Beta-HCG:

Human chorionic gonadotropin

HDAC:

Histone deacetylase

HDACi:

Histone deacetylase inhibitor

HIV:

Human immunodeficiency virus

HMEC:

Human mammary epithelial cell

HMT:

Histone methyltransferases

HP-1:

Heterochromatin protein-1

Hsp90:

90 kDa heat shock protein

IAP:

Intracisternal A-particle

L1Md :

L1 in Mus domesticus

L1Rn:

L1 in Rattus norvegicus

LINE-1 or L1:

Long interspersed nuclear element-1

LTR:

Long terminal repeat

MBD:

Methyl binding protein

MGST 1:

Microsomal glutathione S-transferase 1

mVSMC:

Murine vascular smooth muscle cells

NAC:

N-Acetyl-L-cysteine

N-CoR:

Nuclear receptor co-repressor 1

nnRTI:

Non-nucleoside reverse transcriptase inhibitor

Nrf-2:

Nuclear factor erythroid 2-related factor 2

nRTI:

Nucleoside reverse transcriptase inhibitor

ORF:

Open reading frame

PAH:

Polycyclic aromatic hydrocarbon

PER:

Period circadian protein

PCAF:

p300/CBP-associated factor

PLZF:

Promyelocytic leukemia zinc finger protein

PML:

Promyelocytic leukemia

RAR:

Retinoic acid receptor alpha

RB:

Retinoblastoma

RP2:

Retinitis pigmentosa

RT:

Reverse transcriptase

RUNX:

Runt-domain transcription factor

SGPL1:

Sphingosine phosphate lyase 1

SIM:

Single-minded protein

SINE:

Short interspersed nuclear elements

siRNA:

Small interfering RNA

SP-1:

Specificity protein 1

SynBP:

Syndecan binding protein

TCDD:

2,3,7,8 Tetrachlorodibenzo-p-dioxin

TERT:

Telomerase reverse transcriptase

WT1:

Wilms’ tumor suppressor

YY1:

Yin yang 1

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Delia Baxter Bldg, Suite 221, 580 Preston Street, Louisville, KY, 40202, USA

    Kenneth S. Ramos, Ivo Teneng, Diego E. Montoya-Durango, Pasano Bojang, Mark T. Haeberle, Vilius Stribinskis & Ted Kalbfleisch

  2. Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Delia Baxter Bldg, Suite 221, 580 Preston Street, Louisville, KY, 40202, USA

    Kenneth S. Ramos & Ted Kalbfleisch

  3. Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Delia Baxter Bldg, Suite 221, 580 Preston Street, Louisville, KY, 40202, USA

    Kenneth S. Ramos, Irma N. Ramos & Ted Kalbfleisch

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  1. Kenneth S. Ramos
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Correspondence to Kenneth S. Ramos .

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  1. School of Medicine and Public Health, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, University Avenue 1400, Madison, 53706, Wisconsin, USA

    Randy L Jirtle

  2. National Institute of Environmental Hea, NIEHS, National Institutes of Health, Research Triangle Park, 27709, North Carolina, USA

    Frederick L. Tyson

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Ramos, K.S. et al. (2013). The Intersection of Genetics and Epigenetics: Reactivation of Mammalian LINE-1 Retrotransposons by Environmental Injury. In: Jirtle, R., Tyson, F. (eds) Environmental Epigenomics in Health and Disease. Epigenetics and Human Health. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-23380-7_6

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