Download Chromatin Impacts on Human Genetics

Chromatin Impacts
in Human Genetics
Chromatin-mediated influences
• Gametic (parental) imprinting
• Regulation of gene expression
• Developmental programming
Gametic (parental) imprinting
• Gametic imprinting is the differential
expression of gene that depends on which
parent donated the gene
• Most genes are expressed from both
maternally and paternally inherited
chromosomes.
• However, some genes are expressed only
from the maternally inherited allele, whereas
others are expressed only from the paternally
inherited allele.
Successful development requires
both maternal and paternal genes
Diseases tracked to imprinting
Prader Willi Syndrome
• Small hands and feet
• Underactive gonads,
tiny external genitals
• Short stature
• Mentally retarded
• Slow-moving
• Compulsive overaters
• Obese
Diseases tracked to imprinting
Angelman Syndrome
• “Happy puppet”
• Severe mental
retardation
• Absence of speech
• Happy disposition
• Excessive laughing
• Hyperactive, with jerky
repetitive motions
• Red cheeks, large jaw
and mouth
Patterns of inheritance
Both diseases are associated with deletions in
the same region of chromosome 15
Parental Origin
Mother
Father
Phenotype
Normal allele
Normal allele
Normal
Normal allele
Deletion
Prader-Willi
Deletion
Normal
Angelman
Genes in imprinted region of Chr 15
Blue: Prader Willi gene candidates
Failure to inherit a good allele from dad results in disease.
Paternal allele is expressed. Maternal allele is silent.
Pink: Angelman gene candidates
Failure to inherit a good allele from mom results in disease
Maternal allele is expressed. Paternal allele is silent.
Gametic imprinting is epigenetic
• For imprinted genes, one allele is
expressed and the other is silent.
• The silent alleles typically show high
levels of DNA methylation and tightly
packed chromatin, consistent with their
transcriptional inactivity.
• The expressed alleles are unmethylated
and associated with loosely packed
chromatin.
What we don’t know about imprinting
• What targets a gene for imprinting?
– Why are some genes expressed from both
alleles and other expressed from only one
allele?
• How are the imprints imposed?
– Do males and females have different
mechanisms for imprinting genes?
Rett Syndrome
•
•
•
•
Nature Genetics (1999) 23:127-128
X-linked trait
Mainly girls affected
Normal at birth
At 6-18 months, begin
losing purposeful
movement
• Persistent wringing of
hands
• Loss of speech, gait
• Mental retardation
ensues
Rett’s is due to defect in MeCP2
• Methyl-cytosine binding protein 2 (MeCP2) binds
methylated DNA and recruits binding of a histone
deacetylase
• Normal role is tightening chromatin packing, leading
to gene silencing
Why is the phenotype neurological?
• The phenotype suggests that the
targets are genes in the brain
• Normal neurological differentiation
requires silencing of MeCP2 gene
target(s)
• The target(s) of MeCP2 are not known
• Mice have a gene
that is homologous
to MeCP2
• Knocking out the
gene in mouse gives
a phenotype similar
to human Rett’s
• This model offers
good experimental
system for studying
the human disease
Nature Genetics (2001) 27:332-336
Mouse model for Rett’s
Male mice with MeCP2 knockout
develop normally for a while (middle),
but at 6 weeks of age, they begin to
develop neurological symptoms, such
as hindlimb clasping (right).
Coffin Lowry Syndrome
• X-linked trait
• Girls less affected than
boys
• Mild to severe mental
retardation
• Poor motor coordination
• Defects in formation of
head and hands
• Not all patients show all
symptoms
Coffin Lowry defect in Rsk2 gene
• Rsk2 codes for a protein kinase, which
phosphorylates proteins that participate in stimulating
cell division and cellular differentiation.
• The Rsk2 protein associates with a histone
acetyltransferase. Together, these proteins
phosphylate and acetylate histone H3.
• Modification of histone H3 is associated with
activation of a suite of genes, whose identity is not
yet known.
• When Rsk2 is not functional, expression of the target
genes is repressed, thus leading to disease.
Chromatin and Cloning
• During differentiation of
cells, many changes in
chromatin occur.
• Cloning from adult cells
requires re-programming to
return the cell to an
embryonic state.
• Re-programming requires
erasing the differentiationspecific chromatin changes.
Cloning anomalies
• Initial successes in cloning are being reevaluated.
• Observations include:
– Dolly, the first cloned sheep, at age 5 years
is fat.
– Cloned mice also tend to be overweight.
– Some cow clones have been born with
abnormally large hearts and lungs.
The cloning process
www.bioteach.ubc.ca
What’s the problem with cloning?
• After nuclear transfer, the donor nucleus often
fails to re-establish an embryonic pattern of
gene expression.
• New studies from R. Jaenisch’s lab show that
this is due to the differentiation and DNA
methylation state of the donor nuclei.
– Neural stems cells make better donors than
differentiated neural cells.
– Cells from DNA methylation mutants make better
donors than normal cells.
• Conclusion: Successful cloning requires reprogramming of chromatin modifications.
Summary
• Chromatin modifications play key roles
in many important processes.
– Parent-of-origin (imprinting) differences in
gene expression
– Activation and repression of gene
expression during development
– Differentiation of cells during development
• Disruption of normal chromatin
modification can result in disease.