Lecture 16 - Epigenetic Inheritance Flashcards
Epigenetic Inheritance
Heritable changes not due to changes in DNA sequence
Major mediators of epigenetic effects
o DNA methylation
o Chromatin modifications
o Non-coding RNAs
Human Health Relevance
o X chromosome inactivation
o Genetic imprinting
o Transgenerational and metastable alleles that may be sensitive to environmental influences
Dosage Compensation
Equalization of gene expression b/w XX and XY
• X chromosome – 155 Mb, 1098 genes
• Y chromosome – 51 Mb, 86 genes
Structural changes that affect X chromosome activity
• Active X
o Euchromatin – active chromatin marks
o Low levels of methylation at promotor CpG dinucleotides
• Inactive X
o Heterochromatin – repressive chromatin marks
o Promoter CpG methylation
Lyon Hypothesis
Females are mosaics of two cell types.
- Condensed X found in somatic cells is transcriptionally inactive
- Inactivation occurs in blastomeres early in embryonic development
- Inactivation is random and irreversible in mitotic descendants
Timing of X inactivation
Occurs independently in each XX cell of the inner cell mass at the blastocyst stage of embryonic development.
• X inactivation occurs randomly at the blastocyst stage
o Each XX cell independently inactives an X
• X inactivation is one reason cloned mammals are not perfect matches
o X chromosome may not be reprogrammed during animal cloning
o Step 1 – remove egg nucleus
o Step 2 – replace egg nucleus w/ one diploid somatic cell nucleus (one xa & one xi)
o Step 3 – implant into female reproductive tract for embryonic development
X Inactivation Mechanism
- Initiation requires counting, selecting, inactivating
- Establishment, spreading of inactivation from “inactivation center”
- Maintenance during subsequent mitotic divisions
Step 1 - Initiation of X inactivation
• Initiation – requires counting, selecting, inactivating
o Counting- always one active X per set of autosomes
Blocking model of X chromosome inactivation
o Selection requires Xist RNA transcribed from the X inactivation center (XIC)
Xist – inactivating agent, 17 kb, polyadenylated, nuclear noncoding RNA
Necessary and sufficient for inactivation of the X form which it is transcribed
Prior to selection in blastomore, Xist and Tsix are transcribed on both chromosomes
During selection, Xist and Tsix “silence” each other
• Xist prevails on inactive X and Tsix prevails on active X
Selection complete
• Xist transcribed from Xi, Tsix no longer expressed
o Xist physically coats the inactive X
Step 2 - Spreading of X inactivation
o Spreading of inactivation starts at XIC Xq13
o Transcribed from XIC on Xi
o Xist RNA coats Xi
o Required for spreading
o This can inactive a translocation that was put on the X chromosome
Step 3 of X inactivation
Maintenance of Methylation
Expressivity of XLR in heterozygous females
o Variable, depends on extent and pattern of Xi
o Nephrogenic diabetes insipidus (AVRP2 locus)
~1% heterozygous females have symptoms as severe as males
o Fragile X (FMRP1 locus)
~30% carriers have ID
o Duchenne and Becker muscular dystrophy (Dystrophin gene)
Variable traits in carriers
Skewing
• Skewing can affect expression of XLR traits in females depending on X inactivation pattern
o Skewing of inactive Xm and Xp may occur by chance (>80% one X active)
o X chromosome lesions can significantly skew ratios of inactivated Xm and Xp
Abnormal X is selected against during development and the configuration that inactivated the abnormal X predominates
Turner Syndrome
45,XO; 1 in 4000 females
o Short stature, webbing of neck, amenorrhea, normal intelligence
Klinefelter syndrome
47, XXY; 1 in 1000 males
o Tall, hypogonadism, some learning difficulties
Other karyotypes: 48, XXYY; 48, XXXY, 49, XXXXY
Trisomy X
47, XXX; 1 in 1000 females
o Tall, variably reduced intelligence
o May be fertile
If X inactivation occurs, why is there a phenotype with an aneuploidy of the X chr?
• Extra X aneuploidy has a phenotype b/c ~15% of genes on the X normally escape inactivation
