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Genomic Imprinting: A Paradigm for Epigenetics of Human Diseases

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Epigenetic Epidemiology

Abstract

Genomic imprinting is a remarkable phenomenon through which certain genes show monoallelic expression depending on their parent of origin. While imprinting may have evolved for viviparity and potentially as a mechanism to balance resource allocation in mammals, functional haploidy presents a clear risk to human health. Both epigenetic and genetic and aberrations at imprinted loci contribute to genomic imprinting disorders, such as Beckwith–Wiedemann, Silver–Russell, Prader–Willi and Angelman syndromes. Beyond these well-documented disorders, changes in the tissue-specific expression levels of imprinted genes may contribute far more widely to human disease. The expression of imprinted genes can be disrupted at the level of a single gene, at the level of an imprinted domain or through changes in imprinted gene networks. Importantly, imprinted genes can respond to prenatal adversity leading to persistent changes in gene expression. Consequently, in addition to identifying the functions of individual imprinted genes, it is important to understand the mechanisms through which imprints are established, maintained and erased, with erasure critical to ensure comprehensive erasure of epimutations in the germline. We review the critical aspects of genomic imprinting and imprinted human diseases as a paradigm for future studies on epigenetics of human development and disease.

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Abbreviations

5hmC:

5-Hydroxymethylcytosine

5mC:

5-Methylcytosine

Airn :

Antisense Of Igf2R non-protein coding RNA

Ascl2 :

Achaete-scute family bHLH transcription factor 2

BWS:

Beckwith–Wiedemann Syndrome

Cdkn1c :

Cyclin-dependent kinase inhibitor 1c

CpG:

Dinucleotide CG

CTCF:

CCCTC-binding factor

Dio3 :

Iodothyronine Deiodinase 3

Dlk1 :

Delta Like Non-Canonical Notch Ligand 1

DNMT1:

DNA methyltransferase 1

DNMT3A:

DNA methyltransferase 3A

DNMT3B:

DNA methyltransferase 3B

DNMT3L:

DNA methyltransferase 3L

(E):

Embryonic

ERVK:

Endogenous retrovirus-K

gDMR:

Germline differentially methylated region

Gnas :

GNAS (guanine nucleotide binding protein, alpha stimulating) complex locus

Grb10 :

Growth factor receptor-bound protein 10

H19 :

H19 gene

H3K27me3:

Histone H3 lysine 27 trimethylation

H3K36me2/3:

Histone H3 di/trimethylated at lysine 36

H3K4me2/3:

Histone H3 di/trimethylated at lysine 4

HELL2:

Helicase, lymphoid specific

HELLP:

Haemolysis, elevated liver enzymes and low platelet count

IC:

Imprinting centre

Igf2 :

Insulin-like growth factor 2

Igf2r :

Insulin-like growth factor 2 receptor

IGN:

Imprinted gene network

IMAGe:

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies

Inpp5f-v2 :

Inositol polyphosphate-5-phosphatase F variant 2

Ins2 :

Insulin 2

Kcnq1ot1 :

Kcnq1 opposite strand/antisense transcript 1 (non-protein coding) gene

KvDMR:

DMR in the Kcnq1ot1 locus

LBW:

Low birth weight

LTR:

Long terminal repeat

Mcts2 :

Malignant T cell amplified sequence

Meg3 (aka Gtl2):

Maternally expressed 3

Mest (aka Peg1):

Mesoderm-specific transcript

MLID:

Multilocus imprinting disorders

Nap1l5 :

Nucleosome assembly protein 1-like 5

NLRP5:

NLR family pyrin domain containing 5

NSD1:

Nuclear receptor binding SET domain protein 1

Peg1 :

Paternally expressed gene-1

Peg3 :

Paternally expressed gene-3

PGCs:

Primordial germ cells

Phlda2 :

Pleckstrin homology-like domain, family A, member 2 gene

PIWI:

P-element induced Wimpy testis

Plag1 (aka Zac1):

Pleiomorphic adenoma gene-like 1

Rasgrf1 :

Ras protein-specific guanine nucleotide releasing factor 1

sDMR:

Somatic differentially methylated region

SETD2:

SET domain containing 2, histone lysine methyltransferase

SETDB1:

SET domain bifurcated histone lysine methyltransferase 1

Slc22a18 :

Solute carrier family 22, member 18

Slc22a2 :

Solute carrier family 22 member 2

Slc22a3 :

Solute carrier family 22 member 3

Slc38a4 :

Solute carrier family 38 member 4

Snrpn :

Small nuclear ribonucleoprotein polypeptide N

SRS:

Silver–Russell Syndrome

TAD:

Topologically associating domain

Tet:

Ten-eleven translocation protein

TNDM:

Transient neonatal diabetes mellitus

TRIM28:

Tripartite motif containing 28

UHRF1:

Ubiquitin like with PHD and ring finger domains 1

UPD:

Uniparental disomy

ZFP:

Zinc-finger protein

Zrsr1 (aka U2af1-rs1):

Zinc finger (CCCH type), RNA binding motif and serine/arginine rich 1

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Acknowledgments

M.A.S. is supported by Wellcome Trust grant 209475/Z/17/Z, L.L. is supported by CIHR grant PJT-165992 and R.M.J is supported by BBSRC grant BB/V008684/1. The authors are grateful to the wider imprinting community—both those whose work is directly covered and the many studies which we have not been able to include due to space constraints. Help with Fig. 8.1 from F. M. John.

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  1. Cardiff School of Biosciences, Cardiff University, Cardiff, UK

    R. M. John

  2. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

    L. Lefebvre

  3. Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK

    M. A. Surani

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  1. R. M. John
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  2. L. Lefebvre
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  3. M. A. Surani
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Correspondence to M. A. Surani .

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  1. Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, USA

    Karin B. Michels

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John, R.M., Lefebvre, L., Surani, M.A. (2022). Genomic Imprinting: A Paradigm for Epigenetics of Human Diseases. In: Michels, K.B. (eds) Epigenetic Epidemiology. Springer, Cham. https://doi.org/10.1007/978-3-030-94475-9_8

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