EPIGENETICS AND GENOMIC IMPRINTING


EPIGENETIC MODIFICATIONS

ACTIVE VS REPRESSED CHROMATIN

Modification of core histones at N-termini.

Methylation of DNA at CG dinucleotides - silences genes.

HETEROCHROMATIN: linage appropriate genes, pericentric DNA, telomeres, repeats - it is highly mentholated and inactive.

EUCHROMATIN: Lineage, appropriate/houskeeping genes, unmethylated but acetylated.

METHYLTRANSFERASES DNMT1

Maintenance methylation of hemi-methylated strands. KO mouse is lethal in early development

DMT2

tRNA methylase DNMT3a

De novo methylation of un-modified DNA during development

DNMT3b

De novo methylation of un-modified DNA during development

DNMT3L

Oocyte and sperm specific roles, required to establish imprinting in oocytes

N-terminal tales of histones are post-translationally modified.

GENOME IMPRITING

imposes biparental reproduction in mammals.

Epigenetic marks are set in the germline, maintained during development and are reversible for resetting in the next generation.

Results in the unequal expression of the alleles of a gene.

Manifests as non-Mendelian inheritance; involved in human disease.

Most genes are expressed from both alleles, imprinted genes are expressed from only one parent and thus are mis-expressed in UPDs.

PRADER-WILLI SYNDROME

15q11-q13

Deletions are transmitted from the father.

Deletions from the mother are asymptomatic.

Central obesity, short stature, small hands and feet, mild facial dysmorphism, always hungry.

Can result from uniparental disomy of Chr15 - two maternally inherited copies of Chr15 (which are turned off) and no paternal copy (which would have been turned on).

Loss of function of paternally expressed genes.

ANGELMAN SYNDROME

15q11-q13

Mutations are transmitted from the mother.

Mutations from the father are asymptomatic.

Happy disposition, inappropriate laughter, widely spaced teeth and wide mouth, stiff, upheld arms and broad stance and mental retardation.

Mutations in a single imprinted gene, UBE3A.

BECKWITH - WIEDEMAN SYNDROME

11p15

De-regulation of imprinted genes.

Sporadic cases and result form epimutations at either of the two imprinting centres.

Shows parent-of-origin-associated prenatal overgrowth and cancer pre-disposition; large tongue (macroglossia), large organs (visceromegaly), large body size (macrosomia), hernia of the navel (omphalocele) and small head (microcephaly).

21% neonatal mortality rate.

Imprinting defects in IVF/BWS are higher than naturally concieved BWS.

SILVER RUSSEL SYNDROME

7p13-p11.2

Low birth rate, decreased birth length, triangular shaped face, postnatal growth retardation, poor appetite/reflux, fifth finger clinodactaly, normal head size appearing large because of small body length and weight.

7% of cases have maternal UPD7, paternal UPD7s are normal, so there are imprinting effects.

ALBRIGHTS HEREDITARY OSTEODYSTROPHY

Chr20

Imprinted GNAS locus. normal parathyroid glands but abnormal renal response to parathyroid hormone, short metacarpals, metatarsals and phalanges, wide bones, thickening of the calvaria.

TRANSIENT NEONATAL DIABETES MELLITUS

Chr6

Epimutation in the imprinted genes PLUS genetic mutations in ZFP57 gene.

Heritable imprinting disorder compatible with life.

Diabetic, cardiac and sometimes even developmental delay.

ZFP57 role in maintenance of imprinted DNA methylation in development.

#genomics

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