epigenetics

human genetics lecture 9

epigenetics

study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence

epigenator

extracellular signal that acts as a trigger

epigenetic initiator

receives signal and establishes the environment / pathway by causing histone or DNA modifications

epigenetic maintainer

sustains chromatin environment in subsequent divisions / generations

DNA methyltransferases (DNMTs)

methylate cytidines at specific regions of DNA, causing long-term gene silencing

histone acetyltransferases (HAT)

acetylate histones to produce euchromatin

histone methyltransferases (HMTs)

methylate histones to produce heterochromatin

PCNA

replication factor that associates with DNMTs, HATs, and HMTs to maintain modifications from one cellular generation to the next

Barr body

silenced X chromosome

dosage compensation

way in which an organism manages gene expression between the sexes when sex chromosomes are unequally present

methods of dosage compensation

• silencing one copy of the X chromosome (in mammals)

• overexpressing the genes in the hemizygous organism

• expressing genes from both copies at 50%

X-inactivation

epigenetic regulation of an entire chromosome in which one of the two Xs is randomly selected to be silenced

Xi chromosome

inactivated X chromosome

Xa chromosome

activated X chromosome

Xist

initiator of X-inactivation, coats entire X chromosome with Xist RNA, triggering DNA methylation

polycomb repressive complex (PRC)

proteins responsible for chromosome-wide silencing

PRC1

mediates ubiquitination on histone protein H2A

PRC2

possesses histone methyltransferase activity and associates with histone protein H3

mosaicism

mixture of features displayed by a heterozygous female due to X-inactivation

human sweat gland development

determined by a gene on the X chromosome, causing sweat glands to exist in a mosaic of functional dominant form and recessive non-functional form

fight or flight response

adrenaline-driven, causes the release of cortisol into the bloodstream

cortisol

stress hormone that is important for freeing stored energy

consequences of excess cortisol

heart disease, depression, increased susceptibility to infection

glucocorticoid receptors (GRs)

receptors that cortisol binds to in the hippocampus

end of stress response

when enough cortisol is bound to glucocorticoid receptors, the hippocampus sends out signals that turn off the stress circuit, shutting down both the fight or flight response and cortisol production

correlation between glucocorticoid receptors and stress response

individuals with higher levels of glucocorticoid receptors are better at detecting cortisol and can recover from stress more quickly

nerve growth factor inducible-A (NGFI-A) protein

transcription factor that activates the expression of NR3C1

NR3C1

glucocorticoid receptor gene

consequence of increase in NGFI-A due to high licking by mother mouse

prevents methylation of the glucocorticoid receptor gene, keeping it accessible for transcription

consequence of mouse not being groomed when it is young

• lower NGFI-A levels

• less NR3C1

• less glucocorticoid receptors are produced

• NR3C1 gets methylated, leading to a long-term decrease in stress response

hongerwinter

children conceived during famine during WWII in occupied regions of the Netherlands grew up to have increased incidents of certain diseases, demonstrating the effect of diet on epigenetics

symptoms of children (F₁) exposed to famine in early gestation (hongerwinter)

• more prone to weight gain

• higher BMI

• higher risk of cardiovascular disease

• higher risk of type 2 diabetes

symptoms of children of children (F₂) exposed to famine in early gestation (hongerwinter)

• increased neonatal adiposity

• higher risk of cardiovascular disease

• higher risk of type 2 diabetes

insulin-like growth factor 2 (IGF2)

• plays an essential role in growth and development before birth

  • studies suggest that it promotes growth and division (proliferation of cells in different tissues

  • there is evidence that it has metabolic functions

inheritance of insulin-like growth factor 2 gene under normal conditions

• only the copy inherited from the father is active (acetylated)

• the copy inherited from the mother is not active (methylated)

inheritance of insulin-like growth factor 2 gene under starvation conditions

• copies inherited from both the father and mother are active

• the body is primed to store more energy and deposit more fat because it expects to be in an environment of resource scarcity

heritable fear of acetophenone in mice

• F₀ is fear-conditioned using acetophenone and mild shocks

• F₁ and F₂ retain that sensitivity, despite never having been exposed to the fear-conditioning

  • they have more odorant receptor neurons in the nose

retained sensitivity to acetophenone in later generations of mice

altered methylation around Olfr151 (M71 receptor gene) in sperm, leading to greater number of M71 neurons in progeny

rate of people affected by PCOS

6-20% of women of reproductive age

symptoms of polycystic ovary syndrome

• irregular or prolonged menstrual cycles

• altered hormone levels (excess androgen → testosterone)

• enlarged ovaries with cysts

percentage of PCOS that is epigenetically inherited

~60%

epigenetic inheritance of PCOS

• pregnant mother that has PCOS releases a hormone into the uterus that seems to reduce the methylation of several genes

• increases the expression of these genes in the daughter

• increases likelihood that the daughter will have PCOS

treatments for PCOS

• addition of methyl groups to affected genes

• hormonal birth control

• Metformin

• anti-androgen (anti-testosterone)

epigenetic reprogramming

histone and DNA modifications are erased during gametogenesis (undo cell differentiation) and during embryogenesis (so that cells are pluripotent)

epigenetics that are not reprogrammed

transgenerational changes and imprinted genes

genomic imprinting

genetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner

imprinted genes

one allele is silenced such that the genes are either expressed only from the allele inherited from the mother or only the allele inherited from the father

maternal imprinting

express only the paternal allele

paternal imprinting

express only the maternal allele

role and genomic imprinting of IGF2 gene

promotes growth, maternally imprinted

role and genomic imprinting of IGF2R (IGF2 receptor) gene

suppresses growth, paternally imprinted

parent conflict hypothesis

• male wants his offspring to survive and be fit (promote offspring growth)

• female needs to make sure she survives which still balancing the needs of her offspring (suppress offspring growth)

uniparental disomy

zygote has both homologous chromosomes from one parent and none from the other

Prader-Willi Syndrome

both copies of chromosome 15 are inherited from the mother

Angelman Syndrome

both copies of chromosome 15 are inherited from the father

characterizations of Prader-Willi Syndrome

children are characterized by:

• obesity due to an insatiable appetite

• small hands and feet

• short stature

• hypogonadism

all individuals are characterized by:

• some level of mental retardation

characterizations of Angelman Syndrome

• severe mental retardation

• severe speech impairment

• unsteady gait

• inappropriate laughter, happiness, and excitability