Chapter 3: Epigenetics and Disease

Transcriptionally silenced genes are said to be __________

"imprinted"

Investigators are studying three major types of epigenetic processes:

(1) DNA methylation (2) histone modification (3) noncoding RNAs (ncRNAs or miRNAs),

Strategies for treatment of epigenetic disease - Pharmaceutical agents may reverse changes associated with disease phenotype: (3)

-DNA demethylating agents: 5-azacytidine (remove methyl groups) -Histone deacetylase inhibitors -miRNA coding (up or down regulated)

Epigenetic Mechanisms

-DNA methylation -Histones -Chromatin -Noncoding RNAs (ncRNAs) -MicroRNAs (miRNAs)

How does someone get Russell-Silver syndrome?

10% of cases are caused by disomy (two copies of a chromosome) inherited from Mom •Downregulation of active IGF-2

DNA demethylating agent

5-azacytidine Remove methyl groups

Fascioscapulohumeral muscular dystrophy (FSHMD)

A mutational contraction at the DUX4 locus, followed by an abnormal epigenetic activation Normal: dense methylation. No mRNA from DUX4 FSHD: Mutational contraction of repeated region. Little or no methylation -> mRNA from DUX4 = FSHD

Histone Acetylation

Acetylation is the process where an acetyl functional group is transferred to a histone. Acetylation removes the positive charge on the histones, thereby decreasing the interaction of the N termini of histones with the negatively charged phosphate groups of DNA. As a consequence, the condensed chromatin is transformed into a more relaxed structure that is associated with greater levels of gene transcription.

A well-known disease example of imprinting is associated with a deletion of about 4 million base pairs (Mb) of the long arm of chromosome 15. When this deletion is inherited from the mother, the child manifests __________

Angelman syndrome.

The epigenetic process that results from attachment of a methyl group to a cytosine is: A.Hypoacetylation B.DNA methylation C.Histone modification D.Transgenerational inheritance

B.DNA methylation

Genomic imprinting is best described as: A. Epigenetic modifications caused by environmental factors B. The heritable transmission to future generations of epigenetic modifications C. Genes are silenced depending on which parent transmits them D. Phenotype is the same whether a given allele is inherited from the mother or the father

B.The heritable transmission to future generations of epigenetic modifications

Another well-known example of imprinting is ______________ syndrome, an overgrowth condition accompanied by an increased predisposition to cancer.

Beckwith-Wiedemann up-regulation, or extra copies, of active IGF2 causes overgrowth in Beckwith-Wiedemann syndrome 20%-30% caused by inheritance of two copies of a chromosome (disomy) from father and no copies from mother

Imprinted

Copy inherited through sperm or egg is inactivated and remains inactive for life

_____________ is, at present, the best-studied epigenetic process

DNA methylation When a gene becomes heavily methylated the DNA is less likely to be transcribed into mRNA.

Fetal alcohol syndrome What can alcohol exposure in utero impact?

DNA methylation states of various genomic elements

miRNAs: Encode small RNA molecules that bind to ends of mRNAs What does this do?

Degrades and prevents translation

Prader-Willi and Angelman syndromes

Deletion of 4 million base pairs of long arm of chromosome 15 •Indistinguishable at DNA sequence level

miRNAs What are they? What do they cause?

Encode small RNA molecules that bind to ends of mRNAs •Degrades and prevents translation

Totipotent

Give rise to ALL cell types of an organism Stem cells

Gregor Mendel's experiments with garden peas demonstrated that... Is this true or now? Why?

Gregor Mendel's experiments with garden peas demonstrated that the phenotype is the same whether a given allele is inherited from the mother or the father. This principle, which has long been part of the central dogma of genetics, does not always hold. For some human genes, a given gene is transcriptionally active on only one copy of a chromosome (e.g., the copy inherited from the father). On the other copy of the chromosome (the one inherited from the mother) the gene is transcriptionally inactive. This process of gene silencing, in which genes are silenced depending on which parent transmits them, is known as imprinting; the transcriptionally silenced genes are said to be "imprinted."

Epigenetics __________ possible target of epigenetic modifications arising through nutritional deprivation

IGF-2

IGF2

Insulin Like Growth Factor 2

Biallelic expression

Maternal and paternal inherited genes contribute to offspring phenotype

Monoallelic expression

Maternal copy randomly chosen for inactivation in some cells, paternal copy in others

A well-known disease example of imprinting is associated with a deletion of about 4 million base pairs (Mb) of the long arm of chromosome 15. When this deletion is inherited from the father, the child manifests ____________

Prader-Willi syndrome.

Histones

Proteins that facilitate compaction of DNA into the nucleus of a cell

Epigenetics Nutrition:

Relationship between nutritional deprivation and disease on one or more generations is largely unknown

Fragile X Syndrome

Results from mutational expansion at the FMRI locus, followed by abnormal epigenetic inactivation mutational expansion of repetitive region -> dense methylation = no mRNA from FMR1 = Fragile X

down-regulation of IGF2 causes the diminished growth seen in ______________ syndrome.

Russell-Silver •10% of cases are caused by disomy inherited from Mom

Epigenetic screening for cancer

Shows promise as a tool for early cancer diagnosis

Fetal alcohol syndrome Treatment with ethanol does what?

Treatment with ethanol impairs cultured stem cells' ability to differentiate to functional neurons

BRCA1 gene

Tumor-suppressor gene (hypermethylated) - some inherited breast cancers

RB1 gene

Tumor-suppressor gene (hypermethylated)- retinoblastoma

pluripotent

Turn in to certain things but not everything

All cells in an individual contain ....

almost same information

Epigenetics modification

alters gene expression without changes to DNA sequence.

Deacetylation

an acetyl group is removed from a histone. Causing a more positive charge on the histones, thereby increasing the interaction of the N termini of histones with the negatively charged phosphate groups of DNA. This causes chromatin to be more condensed and tight. Less transcription occurs

DNA methylation results from...

attachment of methyl group to cytosine

oncogenes

cancer causing genes

Epigenetics In utero exposure to _________ may lead to similar epigenetic modifications

chemicals

Methylation densities decline as tumors progress, which can increase the activity of oncogenes, causing tumors to progress from benign neoplasms to malignancy. Additionally, the promoter regions of tumor-suppressor genes are often hypermethylated. These elevated methylation levels...

decreases their rate of transcription at these critical genes, thus reducing the ability to inhibit tumor formation.

5-azacytidine is a ________. What has it been used for?

demethylating agent has been used as a therapeutic drug in the treatment of leukemia and myelodysplastic syndrome.

Epigenetic modification enables cells to achieve ___________

diverse functions

Russell-Silver syndrome

down regulation: too little IGF2 •Downregulation of active IGF-2 causes diminished growth •Abnormalities with imprinting of chromosome- causes down regulation of IGF2

Events encountered in utero, in childhood, and in adolescence can result in specific ....

epigenetic changes that yield a wide range of phenotypic abnormalities, including metabolic syndromes.

Environmental factors, such as diet and exposure to certain chemicals, may cause ___________

epigenetic modifications.

Epigenetics Maternal Care: Alteration to methylation states could help explain why...

exposure to stress early in life can modulate behavior in adulthood

DNA methyltransferase (DNA MTase)

family of enzymes catalyze the transfer of a methyl group to DNA

Manifestations of Prader-Willi syndrome if inherited from _______. What are they?

father Short stature, hypotonia (low muscle tone), small hands and feet, obesity, mentally challenged

Both abnormal gain of methylation, as in the case of ____________. And abnormal loss of methylation, as in the case of __________, can produce disease phenotypes.

fragile X syndrome FSHMD: Facioscapulohumeral muscular dystrophy

Fragile X syndrome Arises through... What specifically happens?

gain of abnormal methylation •Large cytosine-guanine (CG) repeat in FMRI promoter

Histone acetylation and deacetylation are essential parts of ___________

gene regulation

Tumor cells typically exhibit ________

genome-wide hypomethylation (loss of the methyl group)

Russell-Silver syndrome Characteristics:

growth retardation, short stature, leg length discrepancy, small, triangular face

When an allele is imprinted, it typically has ___________

heavy methylation. By contrast, the nonimprinted allele is typically not methylated. = displayed in phenotype

Specific genes are expressed only in the cells and tissue types in which their gene products typically function •Factor VIII expression in ________

hepatocytes

Histone modifications include...

histone acetylation and deacetylation to the end of a histone protein

The best evidence for epigenetic effects on disease risk comes from studies of __________

human cancer.

Methylation densities decline as tumors progress, which can increase the activity of oncogenes, causing tumors to progress from benign neoplasms to malignancy. Additionally, the promoter regions of tumor-suppressor genes are often ________

hypermethylated

Tumor-suppressor genes are often _________ Examples:

hypermethylated (increase in the epigenetic methylation) •RB1 gene—retinoblastoma •BRCA1 gene—some inherited breast cancers

Genomic Imprinting For some human genes, a given gene is transcriptionally inactive on only one copy of a chromosome •Example: Copy inherited from father is active while copy inherited from mother is __________

inactive (silenced)

Genetic conflict hypothesis: Imprinting of paternally inherited genes tends to ...

increase offspring size

As twins age, they demonstrate ...

increasing differences in methylation patterns of their DNA sequences, causing increasing numbers of phenotypic differences.

omphalocele

infant's intestine or other abdominal organs are outside of the body because of a hole in the belly button (navel) area Occurs in Beckwith-Wiedemann syndrome

Methylation, along with histone hypoacetylation and condensation of chromatin...

inhibits the binding of proteins that promote transcription, such that the gene becomes transcriptionally inactive.

Factor VIII expression

is an essential blood-clottingprotein. In humans, factor VIII is encoded by the F8 gene. expression in hepatocytes

In studies of twins with significant lifestyle differences (e.g., smoking versus nonsmoking) ...

large numbers of differences in their methylation patterns are observed to accrue over time.

Fragile X syndrome arises through gain of abnormal methylation. •Large cytosine-guanine (CG) repeat in FMRI promoter Disease can be present in males with:

large repeat of cytosine-guanine (CG) and absent in others with similar large repeats

Fascioscapulohumeral muscular dystrophy (FSHMD) Arises through... What specifically?

loss of normal methylation •Deletion of a nucleotide repeat in the DUX4 gene

Oncomires

miRNAs that stimulate cancer development

Hypermethylation also is seen in __________ genes and is associated with __________.

microRNA tumorigenesis

Aberrant methylation can lead to... (Aberrant= departing from an accepted standard)

misregulation of tumor-suppressor genes and oncogenes (oncogenes= cancer causing genes)

Manifestations of Angelman syndrome if inherited from _________. What are they?

mother •Severely mentally challenged, seizures, ataxic gait (abnormal, uncoordinated movements)

Specific genes are expressed only in the cells and tissue types in which their gene products typically function •Dopamine receptor expression in __________

neurons

nonimprinted allele is typically _________

not methylated

Methylation densities decline as tumors progress, which can increase the activity of _____________, causing ...

oncogenes, causing tumors to progress from benign neoplasms to malignancy. Oncogenes= cancer causing genes

Genomic Imprinting For some human genes, a given gene is transcriptionally inactive on ...

only one copy of a chromosome

miRNAs When microRNA genes are methylated, their mRNA targets are _____________. Associated with __________

overexpressed metastasis

Unlike DNA sequence mutations, epigenetic modifications can be reversed through ___________ For example:

pharmaceutical intervention 5-azacytidine, a demethylating agent, has been used as a therapeutic drug in the treatment of leukemia and myelodysplastic syndrome.

Genetic conflict hypothesis: Imprinting of maternally inherited genes tends to ....

reduce offspring size

Fetal alcohol syndrome Ethanol exposure in utero may ...

repress fetal expression of the DNA methyltransferases (DNA methyltransferases= family of enzymes catalyze the transfer of a methyl group to DNA.)

Fetal alcohol syndrome, which results from ethanol exposure in utero, may be mediated by the ....

repressive impact of ethanol on the DNA methyltransferases.

(3) noncoding RNAs (ncRNAs or miRNAs),

short nucleotides derived from introns of protein coding genes or transcribed as independent genes from regions of the genome whose functions, if any, remain poorly understood. MicroRNAs regulate diverse signaling pathways.

Fragile X syndrome Arises through gain of abnormal methylation •Large cytosine-guanine (CG) repeat in FMRI promoter Acquisition of methylation-based silencing at FMRI is ___________

stochastic (randomly occurring)

When a gene becomes heavily methylated...

the DNA is less likely to be transcribed into mRNA renders genes silent

Specific genes are expressed only in...

the cells and tissue types in which their gene products typically function

(2) histone modification

through the addition of various chemical groups, including methyl and acetyl to the histone = causes changes in the tightness/looseness the chromatin is. This affect transcription.

The heritable transmission to future generations of epigenetic modifications is called __________

transgenerational inheritance.

Methylation densities decline as ___________

tumor progress

Beckwith-Wiedemann syndrome

up regulation: too much IGF2 •Overexpression (extra copies) of active insulin-like growth factor 2 (IGF-2)

(1) DNA methylation

which results from attachment of a methyl group to a cytosine; in the somatic cells, all or nearly all methylation occurs at cytosines that are followed by guanines ("CpG dinucleotides")

How does someone get Beckwith-Wiedemann syndrome?

•20%-30% caused by inheritance of two copies of a chromosome (disomy) from father and no copies from mother- got both from dad •Overexpression (extra copies) of active insulin-like growth factor 2 (IGF-2)

Fetal alcohol syndrome

•Alcohol exposure in utero can impact DNA methylation states of various genomic elements •Treatment with ethanol impairs cultured stem cells' ability to differentiate to functional neurons •Ethanol exposure in utero may repress fetal expression of the DNA methyltransferases

Chromatin

•DNA in association with histones •Critical role in determining development of cells

Housekeeping genes remain transcriptionally active in almost all cells

•Encoding histones •DNA and RNA polymerases •Ribosomal RNA genes

Genetic conflict hypothesis:

•Imprinting of maternally inherited genes tends to reduce offspring size •Imprinting of paternally inherited genes tends to increase offspring size

Beckwith-Wiedemann syndrome Manifestations present at birth:

•Large for gestational age, neonatal hypoglycemia, large tongue, creases on earlobe, omphalocele (infant's intestine or other abdominal organs are outside of the body because of a hole in the belly button (navel) area.) •Increased predisposition to cancer! Causes cancer to grow faster because it as too much IGF2

MicroRNAs (miRNAs)

•Modulate the stability and translational efficiency of existing messenger RNAs •Specific and general •Oncomires -miRNAs that stimulate cancer development

DNA methylation

•Results from attachment of methyl group to cytosine •Renders genes silent •Prominent role in health and disease •Aberrant methylation can lead to misregulation of tumor-suppressor genes and oncogenes •When a gene becomes heavily methylated, the DNA is less likely to be transcribed into mRNA

Noncoding RNAs (ncRNAs)

•Role in RNA splicing and DNA replication •"Sop up" complementary RNAs