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L18 - Epigenetis III Understand that epigenetic mechanisms contribute to…
L18 - Epigenetis III
- Understand that epigenetic mechanisms contribute to cancer pathogenesis
- Be able to describe the difference between monoallelic and biallelic gene expression
- Be able to describe genetic imprinting, the mechanisms involved & examples of imprinting diseases
- Be able to describe X inactivation and the mechanisms involved
- Understand that X inactivation may be skewed
- Understand that monoallelic expression can occur without genetic imprinting
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Genomic Imprinting
Imprinting = The simultaneous
expression of one allele, and the repression of it's parentalcounterpart allele across maternal/paternal chromosomes
*In mammals estimate 70-200 genes different - may be
methylated in eggs and unmethylated in sperm
Offspring may inherit an inactive (methylated) copy and an active
(demethylated) copy of each gene, called genomic imprinting*
Imprinted (Monoallelism)
So, even though two copies of a
gene are inherited (one
from each parent), during Monoallelic expression only one, either the
maternal or paternal allele, is
expressed.
– The non-expressed allele is said
to be “imprinted”
*Not all monoallelic expression is imprinted from the same parent of origin, it's often random
Heritability of Genomic Imprinting
Imprnting, like DNA is considered information (informing a genome how to express a particular locus)
This "information" (whatever causes the parent-of-origin gene expression) is NOT contained in the DNA sequence.
Genomic Imprinting is Epigenetic
Imprinting is A heritable change of gene expression that is not passed on
through change in DNA sequence
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Biallelic Expression
Most genes (>99%) genes are expressed from
both parental alleles (e.g. bi-allelelic expression).
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Imprinting Disorders
These diseases are characterised by non-Mendelian inheritance yet are also inheritance patterns consistent with parent-origin effects
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Angelman and Prader-Willi syndromes
Both involve imprinting defects at 15q11-q13
1. Deletion from paternal allele => Prader-Willi syndrome (hypotonia, mental retardation, obesity).
2. Deletion from maternal allele => Angelman sydrome (severe mental retardation, movement disorder, seizures).
Angelman syndrome:
- Severe mental retardation, microcephaly, lack of speech, frequent laughter.
- Deletion of maternal 15q11-q13
Loss of maternal UBE3A gene
Phenotypes:
- Developmental delay, severe mental retardation, lack of speech,
- movement ataxia, hyperactivity.
- Seizures, aggressive behaviour and excessive and inappropriate laughter
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Prader-Willi syndrome:
- Mild mental retardation, obesity, short stature.
- Able to skip several generations of female offsprig before reappearing in the progeny of a carrier father
- Deletion of paternal 15q11-q13
Deficient snoRNAs expression of paternal allele
Phenotypes:
- Hypotonia, respiratory distress and failure to thrive in postnatal period,
- Hyperphagia in early childhood, resulting in obesity.
- Short stature, small hands and feet,
- Mild-moderate mental retardation, temper tantrums and OCD.
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X Inactivation - Monoallelic expression
Occurs early in the development of most female mammals => Human females are “functionally mosaic”
Most of the genes on one X chromosome are inactivated (by methylation) in every cell (e.g. whole chromosome inactivation).
Mechanism of Dosage Compensation
Overall transcription dosage of Chr X genes is equal in males and females
Takes place early in development
~64 – 128 cell (blastocyst) stage in mouse zygotes
- Exact point is disputed, but most important to note is that it is early in development (~1000 human cells)
Mechanism of X Inactvation
- Inactivation of one X Chr is achieved by XIST (X Inactivation-
Specific Transcript) – an X chromosome-encoded
lncRNA
- Each cell within the early blastocyst makes this binary decision independently of one another
- XIST coats the inactive X chr leading to condensation and heterochromatin conformation (silencing) & methylation
Independent silencing of X-Chromosome
Binary decision to silence maternal/paternal X chromosomes is random, though subsequent progeny maintain the same pattern
Tortoiseshell Cats
- Each fur variant exhibit the same monoallelic-expression pattern as their progenitor cells
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Developmental Origins of Disease
Ever-increasing evidence (epidemiological studies of humans and experimental studies in animals) that exposures in utero, during infancy & childhood result in increased risk of adult onset diseases
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