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Define epigenetics

Chemical modifications to the DNA& DNA-associated structures that do not change the DNA sequence, but can regulate gene expression and can be inherited across mitotic cell division


How can chromatin structure& gene expression be regulated

‣ DNA methylation
‣ Histone modifications
‣ Chromatin-remodeling complexes
‣ Non-coding RNA-mediated gene-silencing
‣ Transcription-factor binding
‣ Mechanisms involved in generating and maintaining
heritable chromatin structure and attachment to the
nuclear matrix.


List some human epigenome atlases

-The ENCODE Project
-NIH Epigenome ROADMAP Project
-The BLUEPRINT Project


What is the significance of 5-methylCytosine (5mC)

-One of the most common and stable epigenetic markers


What are the roles of DNA methylation in normal development and over the life course?

‣ Gene expression regulation
‣ Reprogramming: cell lineage & tissue differentiation
‣ Genomic stability
‣ Genomic Imprinting
‣ X-chromosome inactivation
‣ Human Disease


What are transposable elements?

Transposable elements (TEs) aka "jumping genes" or transposons, are sequences of DNA that move from one location in the genome to another.
-Two types:
1.)· Retrotransposons (class 1)
-Use reverse transposase to make RNA intermediate for transposition.
-Encode an integrase and reverse transcriptase for transposition.
-Found in viruses.
2.) Transposons (class 2)
-DNA fragments transpose directly from DNA segment to DNA segment:


What is genetic imprinting?

-Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner.
-Maternally-imprinted gene: no
expression from maternal copy
-Paternally-imprinted gene: no
expression from maternal copy


What are imprinting disorders?

-Problems with the parent-of-origin expressed allele
1.) Uniparental Disomy (UPD)
-No allele
2.) Deletion/mutations


Outline Prader Willi syndrome

-1 in 10,000-20,000
-Life-threatening obesity
-Early childhood obesity
-Constant hunger
-Infantile hypotonia
-Short stature
-Small hands & feet
-Mild mental retardation
-Mild facial dysmorphism
Can be an eg of an imprinting disorder. Imprinted region on chromosome 15: imprinting is not the cause of disease,
but is responsible for the pattern of manifestation of the disease
-Happens when dad's copy is missing, or when there are two maternal copies.


Outline Angelman syndrome

-1 in 12,000-20,000
-Happy, gregarious nature
-Inappropriate laughter
-Severe mental retardation
-Ataxia, jerky movements
-Large mouth
-Wide-spaced teeth
-Prominent nose
Can be an eg of an imprinting disorder. Imprinted region on chromosome 15: imprinting is not the cause of disease,
but is responsible for the pattern of manifestation of the disease
- Happens when mom's copy is defective or missing, or when there are two paternal copies.


Outline Beckwith-Wiedemann syndrome

-1 in 13,000
-Cancer pre-disposition
-Macrosomia (large birthweight)
-Macroglossia (large tongue), prominent eyes
-Accelerated bone age
-Growth asymmetry
-Enlargement of kidneys, liver, pancreas, and spleen
-Neonatal hypoglycemia (30%)
-Cardiovascular defects


How is genetic imprinting responsible for the pattern of manifestation in PWS or AS

-An individual normally has one active copy of an imprinted gene.
-Improper imprinting can result in an individual having two active copies or two inactive copies.
-Prader-Willi and Angelman syndrome are two very different disorders, but both linked to the same imprinted region of chromosome 15. Some of the genes in this region are silenced in the egg, and at least one gene is silenced in the sperm. So someone who inherits a defect on chromosome 15 is missing different active genes, depending on whether the chromosome came from mum or dad.


How is genetic imprinting linked to BWS

-The Igf2 gene (but not the Igf2 receptor gene) is also imprinted. The Igf2 gene codes for a hormone that stimulates growth during embryonic and fetal development. Methyl tags normally silence the maternal Igf2 gene. But a DNA mutation or an "epimutation" (missing methyl tags) can activate it, resulting in two active copies of the gene.

-Activation of the maternal Igf2 gene during egg formation or very early in development causes Beckwith-Wiedemann Syndrome (BWS).
-Increased incidence of BWS in IVF-conceptions


Outline Silver Russel syndrome

-1 in 75,000
-Prenatal and postnatal growth retardation
-Characteristic facial appearance=a small, triangular face
-Growth asymmetry particularly of limbs
-Small incurved fifth fingers
-Variety of minor malformations


What are the genetic regions responsible for Silver Russel syndrome

Multiple genetic regions
-60%: chr11 (epi)genetic mutations:
-Same region affected in 5-10% of
Beckwith-Wiedemann Syndrome
patients (overgrowth)
-10%: chr7 regions (maternal UPD)
-30%: unknown cause


What is skewed XCI?

-Caused by Cell Selection, Not a General Cellular Defect
-Been associated with haemophilia, Fragile-X
syndrome, and Duchenne Muscular Dystrophy.


What is X chromosome inactivation?

-The random silencing of
one X chromosome in order for
female development to proceed
-Mechanism of dosage compensation
-XCI skewing can occur (eg preferential inactivation of maternal X)
-A recessive mutation carried on the active X chromosome can
have profound adverse phenotypic effects.


What is Developmental Origins of Human Disease Hypothesis (DOHAD)?

-Exposures in development (prenatal, foetal, and postnatal) lead
to greater susceptibility to human disease in later life
-Fetal Origins or Barker Hypothesis: fetal environment and early
infant health permanently programme the body's metabolism and
growth, and thus susceptibility to late onset disease.