Lecture 1

When was Epigenetics first proposed?

first proposed as a solution to the problem of genetics

Genetics:

the study of how, in all livings, the qualities of parents are given to their children through genes

• study of heredity

What does genetics attempt to understand?

attempts to understand phenotype by studying genotype

What is a problem of genetics?

could not understand how the same genotype could produce different phenotypes

True or False: Concordance rates are not 100% for identical twins.

True

True or False: Our phenotypes are stable across development, and our genotype changes.

False, our phenotypes change across development but our genotypes do not

What would be an example of how genotype doesn’t fully explain phenotype?

our somatic cells have the same DNA but these cells look and act differently

How did early geneticists hypothesize genotypes?

hypothesized about genotypes by observing phenotypes

• Mendel → “heritable elements” were thought to be passed down to produce visible qualities

What were the molecular basis of Mendel’s heritable factors?

• molecules need to be transmitted from parents to offspring

• molecules need to be transmitted from fertilized egg to “daughter cells” during cell division

• molecules need to be able to influence the structure and functioning of daughter cells, so that an organism can be built in a species-appropriate way

Difference between geneticists and embryologists:

• geneticists → something in the nucleus

• embryologists → something more than the nucleus

  • less focused on the nucleus/ genes

Ernest Everrett Just:

embryologist that asserted cells posses the ability to respond to complex, physiologically relevant signals acting at the cell surface

• opposed idea that embryo was pre-determined

How can cells with the same genotype have distinct phenotypes?

zygotes divide by mitosis in a process where each cell doubles

• early embryonic stem cells can become any type of cell

• as development proceeds, cells become specified

  • distinct from each other in structure and function

  • same DNA

• once they commit to a particular pathway, they don’t go back

Genetic Restriction Theory:

theory emphasizes that nuclear and cytoplasmic factors interacted

• explained how identical chromosomes could give rise to different cells

• non-genetic cytoplasmic factors contributing to phenotype, neurons store unused DNA

• supported by modern epigenetics data

Morgan’s Gene Theory:

theory suggests that nuclear factors like genes determine cell phenotype

• doesn’t explain how neurons and epithelial cells have the same genotype but different phenotypes

• genes control all events throughout development

Why was Just’s theory of Gene Restriction correct?

developmental processes restrict the use of all genetic material and unused material is “sequestered” in the nucleus

• nuclear and cytoplasmic factors do interact to affect phenotype

The Modern view of Epigenetics:

genotype alone does not determine phenotype

• environmental factors act on genes to determine phenotype

Epigenotype:

paper written by Conrad Waddington in which he called the attention to the lack of any known or hypothesized causal mechanisms that could translate genotype into phenotype

• argued that there must be some level of regulation “over” the level of genes

Epigenetics:

• stable alterations in gene expression without changes to the underlying DNA sequence

  • heritability dissociates epigenetics from neuroepigenetics

• covalent modifications of DNA and histone proteins that exists “over” DNA and influence gene expression

• regulatory mechanisms should persist in the absence of the original signal

Why can’t genotype explain phenotype?

genotype can’t explain phenotype because not all genes in a cell are used or expressed

How does phenotype arise from genotype?

• after cells differentiate they lose pluripotency → access to be whatever they want

  • don’t lose genetic material

• transcription factors proteins regulate gene expression patterns

  • TFP regulated by intrinsic and extrinsic signals

True or False: Cells become different during development when cell-specific gene expression patterns are set by Transcription Factor Proteins.

True

Transcription factors:

proteins that determine which genes are active and when

• bind to regulatory elements or specific DNA sequences to regulate transcription

How can cells become different during development when cell-specific gene expression patterns are set by Transcription Factor Proteins?

transcription factors can turn genes on/off by binding to specific DNA sequences to activate or repress them

Enhancers:

transcription factor binding sites that may be any distance from the gene

• DNA looping can be initiated when a TF binds to enhancer element

• TF at enhancers site can facilitate RNA pol. binding at the promoter

What causes the transcription factor to bind?

TF must be turned “on” in order to bind to DNA

• are activated by intrinsic and extrinsic signals

Intrinsic signals:

arise from inside the cell

• presence or absence of proteins, enzymes, etc

Extrinsic signals:

arise from outside the cell → other cells or outside environments

• signaling molecules

  • hormones

  • neurotransmitters

  • etc

Which transcription factor initiates development?

the transcription factors that initiate development are contributed by the mother

• present in the fertilized egg

How does gene expression regulate cell differentiation?

new patterns of expression arise in daughter cells when:

• TF activate genes that encode other TF

• signaling molecules can impact gene expression

  • steroid hormone receptors are ligand-dependent TF

  • neurotransmitter receptor stimulation can activate intracellular enzymes that regulate the activity of TF

True or False: The induction of gene expression by a developmental signal is Epigenetic.

False, The induction of gene expression by a developmental signal is NOT Epigenetic

True or False: The persistence of gene expression patterns in the absence of developmental signals is Epigenetic.

True

Covalent modifications:

each ball is a nucleosome with 2 copies of the 4 histones

• about 147 BP of DNA

Types of Chromatin:

• Heterochromatin → tightly wound and transcriptionally inactive

• Euchromatin → loosely wound and transcriptionally active

Example: Gene X expression sustained in the absence of the developmental signal.

What does it mean by “Once a liver cell always a liver cell”?

What happens when liver cells are generated in adulthood?

1 liver cell can divide into 2 liver cells

• new liver cell looks and acts the same as the original liver cell even though it was never exposed to developmental signals

  • has the same DNA

Why does the issue of heritability dissociate traditional Epigenetics from Neurogenetics?

Neurons do not divide and enhance do not pass down traits/information

What Epigenetic mechanisms do occur in neurons?

• DNA methylation

• Post-translational histone modification

• Chromatin Remodeling

• Non-coding RNAs

• Genome Organization

Epigenetics vs Neuroepigenetics:

• Epigenetics → heritable alterations in gene expression without changes to the underlying DNA sequence

• Nueroepigenetics → persistent alterations in gene expression without changes to the underlying DNA sequence