Epigenetics APRIL 24 AI GENERATED

Flashcards on Epigenetics

Nature vs. Nurture

The idea that both genes and the environment contribute to an individual's traits.

Epigenetics

The interaction between environment and heredity.

The inheritance of changes in gene function without any change in the DNA nucleotide sequence.

Conformational changes to the DNA that can affect gene expression.

The study of the ways in which epigenetic changes alter cell- and tissue-specific patterns of gene expression.

Epigenetic Trait

A stable, mitotically and meiotically heritable phenotype that results from changes in gene expression without alterations in the DNA sequence

Epigenome

Combination of your DNA sequence and your epigenetic alterations

The epigenetic state of a cell..

Genome and Epigenome

An individual has one genome, but this genome can be modified in diverse cell types at different times to produce many epigenomes.

Epigenetic changes can

lead to phenotypic changes throughout the organism's life cycle.

Epigenetics has been implicated in

Progressive restriction of gene expression during development, allele-specific expression in gene imprinting, and environment genome interactions during prenatal development that affect adult phenotypes.

Human genetic disorders caused by abnormal regulation of the epigenome

Prader–Willi syndrome, Angelman syndrome, and Beckwith–Weidemann syndrome.

Cancer

The loss or alteration of epigenetic states.

Three major mechanisms of epigenetic changes

Methylation, Histone modification and chromatin remodeling, and Noncoding RNA (siRNAs and miRNAs).

Methylation

The reversible modification of DNA by the addition or removal of methyl groups

Addition of a methyl group (-CH3) to cytosine on the 5- carbon of the cytosine nitrogenous base resulting in 5- methylcytosine (5mC).

CpG dinucleotides

Methylation occurs on cytosine bases adjacent to guanine called CpG dinucleotides, which are clustered in regions called CpG islands

CpG

Regions where there are CG repeats, NOT CG base pairs.

p in CpG

The phosphodiester bonds linking adjacent bases

CpG islands location

Located in and near promoter sequences adjacent to genes.

CpG Islands are

Adjacent to essential genes (housekeeping genes) and cell-specific genes are unmethylated and available for transcription whereas other genes are methylated and transcriptionally silenced.

Methyl groups occupy

The major groove of DNA and silence genes by blocking the binding of transcription factors and other proteins necessary to form transcription complexes.

The bulk of methylated CpG dinucleotides are found in

repetitive DNA sequences located in heterochromatic regions of the genome including the centromere.

Heterochromatic methylation

Maintains chromosome stability by preventing translocations and other chromosomal abnormalities

Inactivation

X chromosomes in mammalian females are inactivated by converting them into heterochromatin (dosage compensation).

CpG methylation in euchromatic regions

Causes a parent- specific pattern of gene transcription (AKA Imprinting).

Chromatin

Composed of DNA wound around an octamer of histone proteins to form nucleosomes.

Histone Modification

An important epigenetic mechanism of gene regulation.

Amino acids in the N-terminal region of the histones can be covalently modified by acetylation, methylation, and phosphorylation.

Occur at conserved amino acid sequences in the N-terminal histone tails, which protrude from the nucleosome.

Chemical modification of histones

Alters the structure of chromatin, making genes accessible or inaccessible for transcription.

Acetylation by histone acetyltransferase (HAT)

Opens up the chromatin structure, making genes available for transcription.

Removal of the acetyl groups by histone deacetylase (HDAC)

Closes the configuration, silences genes by making them unavailable.

The histone code

The sum of the complex patterns and interactions of histone modifications that change chromatin organization and gene expression.

miRNA

Small, noncoding RNA molecules also participate in epigenetic regulation of gene expression.

miRNA molecules

Associate with protein complexes to form RNA-induced silencing complexes (RISCs).

Recap of Epigenetic Changes

Methylation of promoters, Modifications of histone tails resulting in changes to the structure of chromatin, and Noncoding RNAs.

Monoallelic expression (MAE)

Only one allele is transcribed, while the other allele is transcriptionally silent.

Three major classes of MAE

Parent-of-Origin Monoallelic Expression: Imprinting, Random Monoallelic Expression: Inactivation of the X Chromosome, and Random Monoallelic Expression of Autosomal Genes.

Imprinted genes show

expression of only the maternal allele or the paternal allele.

Imprinting

Differential methylation of CpG-rich regions produces allele- specific imprinting and subsequent gene silencing.

Gene Imprinting

Once a gene has been methylated and imprinted, it remains transcriptionally silent during embryogenesis and development.

Most imprinted genes

Direct aspects of growth during prenatal development.

Encode growth factors or other growth- regulating genes.

Imprinted genes play major roles in controlling growth during embryonic and prenatal development.

In mice

Genes on the maternal X chromosome are expressed in the placenta, but genes on the paternal X chromosome are silenced.

Imprinting in mammals

The pattern of imprinting in mammals is reprogrammed every generation.

When gamete formation begins in female/male germ cells

Both chromosome sets have their imprints erased and are each reprogrammed by changing the pattern of methylation to carry a female/male imprint that is transmitted to the next generation through the egg/sperm.

Patterns of Methylation

methylation are preserved during cell division by maintenance methylases

Reprogramming

Occurs in the parental germ line and in the developing embryo just before implantation.

After implantation

Differential genomic remethylation recalibrates which maternal and paternal alleles will be inactivated.

Most imprinting disorders

Have their origins during fetal growth and development.

Imprinting disorders

Prader–Willi syndrome, Angelman syndrome, and Beckwith–Weidemann syndrome.

Beckwith–Weidemann syndrome (BWS)

A disorder of imprinting that is caused by abnormal patterns of DNA methylation resulting in altered patterns of gene expression.

Enlarged organs, high birth weight and a predisposition to cancer.

Autosomal dominant imprinting disorder that involves the Insulin-Like Growth Factor 2 (IGF2) and H19 loci.

IGF2

A signaling molecule that encourages cell division

H19

A long non coding RNA that opposes cell division

Epigenetic Cause of BWS

If the ICR on both chromosomes is methylated it leads to overexpression of IGF2 and the expression of H19 is silenced then this produces overgrowth of tissues leading to BWS.

Once x is inactivated

The same X chromosome remains silenced in all cells descended from this progenitor cell.

Xist

If Xist RNA is transcribed it binds to the X chromosome causing it to condense and form a Barr body.

If Tsix RNA is transcribed it binds to the Xist locus and prevents it from being transcribed.

Inactivation of Autosomal Genes

Expression of both alleles is biallelic expression, Expression of only the maternal allele and/or paternal allele, and/or Expression of neither allele.

Random inactivation

Related to Monoallelic Expression of autosomal genes (MAE)

MAE first step

The first step appears to be random and occurs early in development, Once established it continues in all subsequent daughter cells, and Two specific histone modifications seem to play an important role.

External factors disturb the epigenetic pattern of imprinting

Embryonic and prenatal development can have serious phenotypic consequences

Children born after IVF and other ART procedures

Are at risk of very low birth weight.

Hypomethylation

Low levels of methylation is a property of all cancers examined to date.

Feinberg and Vogelstein

Observed that colon cancer cells had much lower levels of methylation than normal cells derived from the same tissue.

Altered in cancer cells

Epigenetic changes, including selective hypermethylation (high levels of methylation) and gene silencing.

Example of Epigenetic Change

Silencing of the DNA repair gene MLH1 by hypermethylation is a key step in the development of some forms of colon cancer.

Epimutations

Can be involved in tumor formation alone or in combination with genetic changes

Cancer is

A disease that involves both epigenetic and genetic changes that lead to alterations in gene expression

DNA hypomethylation in cancer

DNA hypomethylation turns on genes, leading to high transcription of many gene sets including oncogenes.

Hypermethylation in cancer

Hypermethylation at CpG islands and inactivation of certain genes are also found in many cancers

Include those involved in DNA repair, differentiation, apoptosis, and drug resistance.

BRCA1

BRCA1 is hypermethylated and inactivated in breast cancer and ovarian cancer

Cancer Forms

The combination of mutation and hypermethylation occurs in familial forms of cancer

Role of Epigenetic Alterations in Cancer

Global hypomethylation may cause genomic instability and the large-scale chromosomal changes that are a characteristic feature of cancer, Epigenetic mechanisms can replace mutations as a way of silencing individual tumor-suppressor genes or activating oncogenes, and Epigenetic modifications can silence multiple genes, making them more effective in transforming normal cells into malignant cells than sequential mutations of single genes.

Cancer cells

show disrupted histone modification profiles and mutations in genes encoding members of the histone- modifying proteins histone acetyltransferase (HAT) and histone deacetylase (HDAC) are linked to the development of cancer

Focus of epigenetic therapy

The reactivation of genes that have been silenced by methylation or histone modification.

Vidaza

Acts as a demethylating agent, removing methyl groups that prevent transcription of tumor suppressor genes

Environmental Agents

Environmental agents including nutrition, chemicals, and physical factors such as temperature can alter gene expression by affecting the epigenetic state of the genome

Epigenetic Drift

DNA methylation patterns that a person is born with can change throughout one’s lifetime

Key Factor in Epigenetic Drift

Environmental exposures are a key factor in epigenetic drift and play a primary role in differences in phenotypic outcomes, disease susceptibility, and disease progression

Monozygotic Twin Studies

Investigate the effects of different environmental influences and Determine if the disease is genetic, random, or a result of environmental exposures

Twin Studies (MZ)

Age, time, and lifestyle differences affect epigenetic drift between twins

Older twins

Those with different lifestyles, and that spent less time together had a greater degree of difference

Inheriting Epigenetic Patterns

Once thought that the only time epigenetic patterns were passed on was during subsequent mitotic cell divisions

Transgenerational Inheritance

Inheritance of post-traumatic stress disorder (PTSD).

PTSD Patients' offspring

Patients who had the lower levels of cortisol excretions and who were diagnosed with PTSD had children with lower levels of cortisol expression

Transgenerational Inheritance

Mothers exposed to the World Trade Center attacks and their infants less than a year old both exhibited lower salivary cortisol levels

Stress

Stress-induced epigenetic changes that occur prenatally or early in life can influence behavior

Stress Induced Behavior

Newborn rats raised with low levels of maternal nurturing (low-MN). Had low Glucocorticoid receptor (GR) expression and as adults did not adapt well to stress, Newborn rats exposed to high levels of maternal nurturing care early in life (high-MN), GR expression is increased, and As adults adapt well to stress.

Low-MN rats with low expression of GR

Had significantly higher levels of promoter methylation.

High-MN rats with high expression of GR

Had low levels of promoter methylation.