Ch.6 - Molecular Mechanisms of Cell Differentiation

Epigenetics

• study of changes/variations in phenotypes that are not caused by permanent changes in DNA base sequences

• potentially heritable

Basis of epigenetics

non-genetic cellular memory

Facultative heterochromatin

regions of chromosomes that contain genes but can become heterochromatic depending on cell type

As cells differentiate what happens to their DNA?

convert more DNA into heterochromatin

Embryonic/adult stem cells have ____ facultative heterochromatin than terminally differentiated cells

less

Transcription regulatory proteins

groups work together to control expression of single genes

What do transcription regulators bind to?

regulatory DNA sequences near genes

What forms the transcription initiation complex?

• transcription regulators binded to regulatory DNA

• general transcription factors

• RNA polyermase

MyoD

transcription regulatory that switches on muscle-specific genes required for specification of skeletal muscle cells

What does MyoD turn cells into?

myoblasts (muscle cell precursors)

MyoD pipeline

MyoD → commits cells to become myoblasts → myoblasts fuse to form multinucleated myotubes → myotubes become muscle fibers

What happens if MyoD is expressed in fibroblasts?

cells start to behave as myoblasts & form muscle-like cells

Transdifferentiation

a mature, differentiated cell type changes directly into a different differentiated cell type

Liver cells can be converted into what via transdifferentiation?

neurons; via artificial introduction of 3 neuron-specific transcription regulators

What happens if Ey is ectopically expressed in larval cells in leg area of Drosophila?

ectopic eye-like structure develops on leg

What is the exception to the rule of terminal differentiation?

epimorphic limb regeneration

What happens in epimorphic limb regeneration?

adult cells in limb wound dedifferentiate to become neoblasts → rapid cell division → neoblasts become re-specified to form missing adult structures

T/F different combinations of a small # of transcription regulators can generate many diff cell types

true

Terminally differentiated cells

only give rise to cells of their own type when dividing; must remember patterns of gene expression that led to differentiation & pass on memory to daughter cells

Mechanisms of epigenetic inheritance

• feedback loop circuits with transcription regulators

• preservation of covalent histone modifications & chromatin condensation patterns

• preservation of DNA methylation patterns

Feedback loop circuits

• signal triggers expression of transcription regulator

• protein perpetuates expression of its own gene by activating own transcription

• cell expression protein must preserve it throughout cell division in order to pass on to daughter cells

• transcription regulator must be able to positively control own transcription even if signal that triggered initial expression is no longer present

How does histone acetylation stimulate transcription initiation?

• acetylation eliminates positive charge on lysine tail in histones

• histones interactions with DNA now weaker (bc + charge on lysine usually interacts with - charge on DNA)

• allows other proteins like transcription factors to bind to DNA

Inheritance of histone modification patterns

• only half of daughter nucleosomes have modified histones after replication of nucleosomes

• tissue-specific histone modifying enzyme preserved throughout cell division

  • enzyme can restore parental patterns of histone modification/chromatin condensation

Methylation of DNA

• occurs on cytosines immediately followed by guanine (CG sequences)

• turn off gene expression by attracting proteins that block transcription

Maintenance of DNA methylation

• only parental strand has methylated cytosines following DNA replication

• enzyme maintenance methyltransferase recognizes already methylated CG sequences & catalyzes methylation of CGs in complementary strand

• enzyme preserved throughout cell division and passed onto daughter cells

de novo methyltransferases

establish new DNA methylation patterns during development

product of Dnmt3 gene

DNA methyltransferase 3; methylates & silences queen-specific genes in worker bees

What does royal jelly do?

silences expression of Dnmt3 gene