DNA Methylation II

maternal genome stays methylated ________ than the paternal genome

longer

changes in DNA methylation during aging in humans

replication errors (mainly stochastic) at cell division

also occur in post-mitotic tissues

allele

one of a number of alternative forms of the same gene or same genetic locus (generally a group of genes)

alternative form of a gene for a character producing different effects

sometimes, different ones can result in different observable phenotypic traits, such as different pigmentation

Barr body

dark, drumstick-shaped masses in nuclei of nerve cells

x-chromosome inactivation

pattern only seen in cats

Lyon hypothesis or Lyonization

condensation of X chromosome mechanism for inactivating the genes on the chromosome

named inactive X chromosome a Barr body

inactivation of X chromosome

genomic imprinting that leads to almost total inactivation of one of the X chromosomes in a female mammalian cell

Xist gene in one of the X chromosomes is expressed (25 kb non-coding RNA) that leads to inactivation of the chromosome (coating, histone modification, heterochromatin, DNA hypermethylation)

Xist gene in the second chromosome is inactive (DNA methylation)- this chromosome remains active

what happens to CpG islands on the inactive X chromosome?

De novo methylation

Xic region on human X chromosome

X-inactivation centre, an uncategorized gene, which contains protein-coding genes and four genes (including Xist) that express non-coding RNA (ncRNA)

characteristics of Xist

located in the XIC region (responsible for cis inactivation)

transcribed only from the future inactive X chromosome (Xi)

20kb cDNA with no open reading frame (ORF)

Xic action results in highly expressed Xist RNA that remains intranuclear, coats the future Xi, surrounds the Barr body

role of antisense transcription in regulation of X-chromosome inactivation

Tsix gene is located 15kb downstream of Xist

Xite functions as an enhancer for development-specific Tsix regulation

Tsix expresses a 40kb ncRNA transcript antisense to Xist RNA

before the onset of X-chromosome inactivation, Tsix is expressed from both X-chromosomes (blocks Xist RNA)

at onset of x-chromosome inactivation, Tsix expression becomes monoallelic:

• on Xa, Tsix RNA blocks Xist RNA

• on Xi, Xist RNA coats the chromosome to repress Tsix expression

inactive X has unacetylated

histone H4

evidence for histone code

transcriptional silencing of the X chromosome correlates with distinct histone modification patterns

e.g. the inactive X chromosome shows reduced H3K4-methylation, then increased H3K27-methylation, followed by decreased H4 acetylation

dosage compensation in cats by

X-inactivation and coat colour mosaicism

all cells in the tortoise cell or calico cats have the same genotype, but

a different copy of the X chromosome is expressed in different cells

X-inactivation in cats

random, during embryonic development causes the patchwork coloured coat in some female cats

this does not occur in males as they only have one X chromosome

mosaicism

an individual with two different eye colours

gene imprinting defects

Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS), transient neonatal diabetes mellitus (TNDM)

trans effects of chromatin related disorders

defects in methylation machinery, defects in histone modification enzymes, cis effects (repeat-instability diseases)

defects in methylation machinery diseases

systemic lupus erythemtosus (SLE), immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, RETT syndrome

defects in histone modification enzymes diseases

Rubinstein-Taybi syndrome, Coffin-Lowry syndrome

cis effects (repeat-instability diseases)

fragile X syndrome (FRAXA), facioscapulohumeral muscular dystrophy

human epigenome project (HEP)

aims to identify, catalogue, and interpret genome-wide DNA methylation patterns of all human genes in all major tissues

methylation is tissue specific and is of major importance in regulation of gene expression during development

working hypothesis for chromatin plasticity and inter-individual phenotypic variance

environment, to epigenetic changes, to inter-individual epigenetic variation, to gene expression programming, to phenotypic variation