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Flashcards in Epigenetic Regulation in Health and Disease Deck (75):
1

Heritable changes in gene function that occurs without a change in the DNA sequence

Epigenetics

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What are some common modifications to the genome?

DNA methylation, Histone Modification, Non-coding RNA

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All of the epigenetic phenomena are characterized by chemical modifications to

DNA itself (DNA Methylation), or to Histones (The proteins around which DNA is wound)

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In humans, DNA methylation typically occurs at the

Cytosine bases of DNA within CpG dinucleotides

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Associated with the 5'-end regulatory regions of almost all housekeeping genes, as well as with half of the tissue specific genes

CpG rich regions ("CpG Islands")

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When these promoter CpG Islands are methylated, the associated genes tend to be

Transcriptionally inactive

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The correct expression of many tissue-specific, germline-specific, imprinted, and X-chromosome inactivated (in females) genes, as well as that of repetitive genomic sequences, relies largely on

DNA Methylation

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Play key roles in the erasure, establishment, and maintenance of DNA methylation patterns through development

Epigenetic modifications

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The extent of DNA methylation changes in an orchestrated way during mammalian development, starting with a

Wave of demethylation during cleavage

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However, after implantation, there is

Genome-wide methlyation

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An active process that strips the male genome of methylation within hours of fertilization

Demethylation

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In contrast, the maternal genome is passively demethylated during subsequent

Cleavage divisions

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The extent of methylation in the genome of gastrulating embryo is high, owing to de novo methylation, but it tends to decrease in specific tissues during

Differentiation

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Occurs rarely after gastrulation, but this phenomenon is seen frequently in cancer

De novo Methylation

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Which enzyme removes methyl groups?

Demethylase (dMTase)

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Which enzyme adds methyl groups

DNA methyl transferase (DNMT)

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Replication of somatic cells results in hemimethylated DNA, which is then fully methylated by

DNMT

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Negatively regulates transcriptional output

Transcription factor binding to methylated DNA sequence motifs

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DNA methylation is important in

1.) Regulation of gene expression (i.e. tissue specific transcription)
2.) Genomic imprinting

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An autism spectrum disorder with a monogenic origin

Rett Syndrome

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A progressive neurological disorder that is one of the most common causes of mental retardation in females

Rett syndrome

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What type of trait is Rett Syndrome?

X-linked dominant

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Children affected by Rett syndrome have a period of apparently normal development lasting

6-18 months

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What is the cause of most cases of Rett Syndrome

MECP2 gene mutations

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Capable of binding specifically to methylated DNA and represses transcription from methylated gene promoters

MECP2

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MECP2 is ubiquitously present, but is most abundantly expressed in the

Brain

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Los of function of MeCP2 in differentiated post-mitotic neurons likely results in the inappropriate overexpression of genes with potentially damaging effects during

Nervous system maturation

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The unequal expression of the maternal or paternal alleles of a gene

Genomic Imprinting

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The epigenetic tags on imprinted genes usually stay put for the life of the organism, but they are reset during

Egg and sperm formation (Thus why they are not passed to offspring)

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Imprinted genes play vital roles in

1.) Embryonic growth
2.) Neonatal behavior
3.) Tissue or developmental stage-specific monoallelic expression patterns

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The SNRPN gene, producing small nuclear ribonucleoprotein N, being methylated during oogenesis but not spermatogenesis is an example of

Genomic imprinting

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An example of genomic imprinting because it is methylated during spermatogenesis but not oogenesis

The UBE3A gene

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Region that contains at least two imprinted genes, one maternally imprinted and one paternally imprinted

Chromosome 15

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If a child receives a chromosome 15 in which a large deletion removed the function of these genes from their father, and an (inactive) maternally imprinted gene from their mother, they will have

Prader-Willi Syndrome

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If a child receives the deleted chromosome 15 from their mother, and an (inactive) copy of the paternally imprinted gene from their father, they will have

Angelman syndrome

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Prader-Willi syndrome is indicated by

Mental retardation and Hyperphagia

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Angelman Syndrome is indicated by

Excessive laughter, seizures, and mental retardation

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In Prader-Willi syndrome, the maternal allele is imprinted by

-No SNRPN protein is expressed from the imprinted maternal chromosome 15 SNRPN allele

Methylation

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In Angelman syndrome, the paternal allele is imprinted by methylation resulting in

-Why a deletion in the mothers gene causes the syndrome

No expression of UBE3A protein by the UBE3A allele

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Histones can be reversibly modified in their amino-terminal tails, which protrude from the nucleosome core particle, by

1.) acetylation of lysine
2.) phosphorylation of serine
3.) methylation of lysine and arginine residues
4.) sumoylation

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The N termini of core histone proteins contain many lysine residues that impart a highly positive charge. These positively charged domains can bind tightly to
the negatively charged DNA through

Electrostatic Interactions

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Tight binding between DNA and histones is associated with

Gene inactivity

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Neutralizes the positively charged histone tails, weakening their interaction with DNA (forming euchromatin) and allowing active transcription

Acetylation of Histone tails

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Which enzyme acetylates histone tails?

Histone acetyltransferase (HATs)

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A functional RNA molecule that is transcribed from DNA but is not translated into proteins

non-coding RNA

-includes: miRNA, siRNA, piRNA, and IncRNA (long non-coding RNA)

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Long non-coding RNAs regulate epigenetics by

Chromatin remodeling, transcriptional regulation, post-transcriptional regulation, and as precursors for siRNAs

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What is an example of epigenetic regulation by long non-coding RNAs (ncRNAs)?

X-chromosome inactivation

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X-chromosome inactivation involves which two IncRNAs?

1.) Xist (of X-inactive specific transcript)
2.) Tsix (its antisense transcript, a negative regulator of Xist)

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Transcribed from the X-inactivation center (XIC) of the inactive X chromosome (Xi)

The lncRNA Xist

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What does the Xist RNA do?

Covers the entire chromosome and silences gene expression through epigenetic modifications of histones and DNA (thus inactivating the X chromosome)

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Can bind to the X-inactive specific transcript (Xist) and inhibit its action, thus preventing X-inactivation

-antisense to Xist RNA

Tsix

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Both chromosomes will express Xist in low concentrations, but then one chromosome will start to express high levels of Tsix, which dratically reduces the concentration of Xist on that chromosome and thus, that chromosome become the

Active X-chromosome

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The ability of one genotype to produce more than one phenotype when exposed to different environements

Phenotypic plasticity

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Environmental effects (such as diet or stress) on a phenotype may involve

Epigenetic changes in gene function

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Changes in chromatin marks and transcriptional networks associated with sustained neuronal activity, mood disorders, and addiciton

Adult Neuronal plasticity and neurogenesis

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Methylation of the agouti gene results inthe agouti mRNA being made briefly during development, before the agouti gene is then silenced for the remainder of the mouses life. This leads to a

Healthy brown mouse

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Non-methylation of the agouti gene results in the agouti gene being continually active, producing mRNA across the mouse's lifespan. This leads to a

Yellow mouse that develops obesity and diabetes during adulthood

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When a female yellow mouse (agouti gene unmethylated) was given a diet supplement during pregnancy and nursing with additional methyl groups, her offspring were

Mostly brown and healthy (agouti gene methylated and silenced)

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When a female yellow mouse (agouti gene unmethylated) was given no dietary supplements during pregnancy, her offspring were

Mostly yellow and unhealthy (agouti gene unmethylated and active)

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What are two methods to study changes in the epigenome?

1.) Bisulfite conversion of DNA
2.) Methylation-sensitive restriction enzymes

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Converts cytidine to uridine if the citidine is NOT methylated

Bisulfite

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Following bisulfite conversion, the DNA strands are no longer complementary and a PCR primer is generated by a reverse transcriptase. Next we perform

PCR, DNA sequencing, or Methylation specific restriction enzyme digestion

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The C's that are not methylated are converted toU's. Then they are replicated by DNA polymerase and become

T's

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We can ditect DNA methylation using methylation-sensitive restriction enzymes. The methylation incensitive restriction enzymes will

Cut DNA next to a methylated C

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Functionally relevant changes to the genome that do not involve a change in nucleotide sequence

Epigenetics

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Epigenetics are cellular and physiological traits that ARE heritable by daughter cells and not cause by changes in

DNA sequence

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Epigenetics describes the study of stable, usually long-term alterations in the

Transcriptional potential of a cell

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These covalent modifications alter how genes are expressed without altering the underlying DNA sequence

-an example of epigenetics

1.) DNA methylation
2.) Histone modifications

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Attach to silencer regions of the DNA and remain associated with the silencer regions subsequent to DNA replication and cell division

Repressor proteins

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Epigenetics may last through cell divisions for the duration of a cell's lie and may also last for multiple generations. These non-genetic factors cause the organisms genes to

Behave (or "express themselves") differently

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Methylation of Cytosine can turn off

Gene expression

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Methylation of CpG in 98% of the genome does not matter. But methylation of the CpG stretches before transcriptional start site,

Inactivates transcription

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If there is an MeCP2 mutation in a boy, they will likely die as a fetus girls survive due to the fact that they have

Two X-Chromosomes

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Inactivation of one of the X-chromosomes is called

Lyonization

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Once you use a methylation-sensitive restriction enzyme technique, you can study the results with

Southern-blot hybridization

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