17. Chromatin Remodeling, Histone Modification, and Methylation and Cell memory

3 mechanisms of transcription regulation

1. Chromatin Remodeling Complexes

2. Histone Modifying Enzymes

3. DNA Methylation

what is a nucleosome

basic structural unit of DNA packaging consisting Histones + DNA

• able to restrict access of transcriptional machinery (TM) to DNA

Altering Chromatin structure/ packing can be done via

1. Chromatin Remodeling Complexes

2. Histone Modifying Enzymes

** allows or disallows DNA access for transcription → regulator

Chromatin-remodeling Protein Complexes

Enzymes that use ATP hydrolysis to alter the physical repositioning of nucleosomes in chromosomes through nucleosome sliding and ejecting

• provides immediate access to specific gene

Histone-Modifying proteins

Enzymes that alters the interaction between histone and DNA

• remove or add covalent modification on the tails of the core Histones (direct modification)

  • acetyl → Loosen via lysine adding neg charge that neutralize the pos charge of histone tail, reducing the affinity for nucleosome

  • phosphate

    • loosen → neg charge for neutralization via serine

    • tighten → attract condensing protein

• recruit chromatin remodeling proteins (indirect modification)

  • methyl groups : serves as a binding site for proteins that can both loosen or tighten the chromatin

• histone modifications are reversible

3 Covalent modification placed by histone modification enzymes are

acetyl, phosphate, or methyl groups

DNA methylation (CH3)

addition of methyl group on the 5’ carbon of cytosine base on CpG site(not histone tail = histone modifying enzyme)

• Methylated CpG → gene repression → recruit condensing proteins

• Unmethylated CpG → gene activation → recruit de-condensing protein

5’ - C G - 3’

CpG site is

target gene for DNA methylation where C falls next to G near promoter w high concentration of CpG site

interphase (cell cycle) Chromosomes

non-uniform packing of chromosome → allows G1 S and G2 phase

• Constitutive Heterochromatin → always condensed / silenced

• Facultative Heterochromatin → able alter accessibility

• Euchromatin → less condensed gene that is actively expressed

X-Inactivation is a form

extreme gene silencing where one of the two X chromosomes in female embryo is randomly silenced permanently

• X-inactivation is irreversible and via an epigentic mechanism

Dosage compensation is

mechanism to equalize the amount of x-chromosome gene expression for males and females through X-inactivation of female embryos

example of dosage compenstation

Kitten born from a mother expressing both Orange and Black will only express black in active X chromosome

• orange gene will not be expressed bc its in the silenced X chromosome

transcription regulator can

recruit appropriate chromatin modifying proteins and chromatin remodeling complexes to initiate transcription

• Activator → recruit complexes that loosens that chromatin

• Repressor → recruits histone deacetylases that removes acetyl group

3 mechanisms of maintaining cell identity

1. Positive feedback loops

2. Histone Modification

3. DNA methylation

Cell memory is

the pattern of gene expression responsible for the cell’s identity to be remembered and passed on to its daughter cells trough all subsequent cell division for a proliferating cell to maintain its identity and function

Methods of keeping Cell Memory: Positive Feedback loop

• master transcription regulator activates its own gene, ensuring its continued presence in daughter cells and sustaining cell identity

  • continued stimulation ensures regulator is distributed to both daughter cells each cell division

Methods of keeping Cell Memory: DNA Methylation

passed on to progeny cells via maintenance methyltransferase

• Template strand after replication carries on the methylation but not the newly synthesized one

• maintenance methyltransferase recognizes this methylated CpG site

• attaches methyl group on the newly synthesized strand

Methods of keeping Cell Memory: Histone Modification Inheritance

• During DNA replication, daughter nucleosomes inherit half of the parent Chromosome’s histones with modifications

  • which are then replicated by histone-modifying enzymes, aiding in maintaining chromatin structure (e.g., heterochromatin).

Epigenetic Inheritance is

patterns of gene expression that are passed on from parent to daughter cells during mitosis without altering the actual genetic sequence of the DNA

• allow cells to "remember" environmental signals, impacting cell function

• potentially contributing to Genetic diseases.