The Molecular Mechanisms of Cell Differentiation

Hematopoiesis

an example of stem cell differentiation

Cell identity memory

when a cell in a multicellular organism becomes committed to differentiate into a specific cell type, the terminal fate is normally maintained through all subsequent generations

a signal triggers changes in gene expression directing a cell toward a particular differentiation pathway

the changes must be remembered for cell division

describe how cell identiy memory works

non-genetic cellular memory

what is the basis of epigenetics?

epigenetics

the study of changes and variations in phenotypes that are potentially heritable, but are not caused by permanent changes in DNA base sequences

Faculative heterochromatin

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

more

As cells differentiate, they convert _____ of their DNA into heterochromatin

embryonic and adut stem cells

what type of cells have less faculative heterochromatin than terminally differentiated cells?

transcription regulatory proteins

proteins that work together to control the expression of single genes

transcription regulators bond to specific regulatory DNA sequence elements near genes, and together with general transcription factors and RNA polymerase form the transcription initiation complex

describe how the transcription initiation complex is formed

some are activators and others repressors, with their effects added up to determine the final level of expression of the gene

describe what is significant about the transcription regulators

transcription levels may be significantly altered or it may not occur at all, because the complex would be incomplete

if any one of these transcription regulators is subtracted from the transcription initiation complex....

single transcription regulator

The expression of a ______________ can be decisive in switching on or off a gene or group of genes

combinatorial; ON

because the effect of transcription regulators is __________, the addition of a single, missing protein can complete a complex that switches a gene _____

completes the transcription intiation complexes regulating several genes, thus switching ON or OFF several genes at once

what can the single transcription regulator also do?

glucocorticoid receptor

a transcription regulator that can actovate the transcription of several genes involved in the glucocorticoid response when the hormone binds to it

Combinatorial controls

controls that can create different cell types

MyoD

the single transcription regulator that switches on the muscle-specific genes required for the specification of skeletal muscle cells

Myoblasts

the muscle cell precursors MyoD commits cells to become

myotubes

myoblasts proliferate and fuse to become multinucleated....

muscle fibers

what do the myotubes become?

fibroblasts

a cell type that belongs to the same broad class of embryonic cells as muscle cells but is involved in wound healing

muscle-like cells

If MyoD is artificially expressed in fibroblasts the cells start to behave as myoblasts and fuse to form....

these cells already contain the other transcriptional regulators required for the combinatorial induction of the muscle fate, and the addition of MyoD completes a unique combination

why can fibroblasts with expressed MyoD form these muscle-like cells?

no

can other cell types not related to muscle cells have this same type of effect as fibroblasts?

the artificial introduction of just 3 neuron-specific transcription regulators that form new combinatorial controls

How do liver cells in culture be converted to neurons?

a single protein can induce the differentiation of all the cell types that are required to assemble an organ

what is another ability of the combinatorial effect being triggered by a single transcription regulator?

Ey

the transcription regulator in Drosophila that controls the expression of many genes that are expressed differentially in all the cell types of the composite eye

an ectopic eye-like structure develops on the leg

what happens if the Ey gene is ectopically expressed in larval cells of the area that gives rise to a leg?

Epimorphic limb regeneration

the process of limb regenration

adult cells in the limb wound dedifferentiate to become neoblasts, rapid cell division occurs, and the neoblasts become re-specified to form the missing adult structures

describe epimorphic limb regeneration

a larger number of genes with shared regulatory DNA sequences

A small number of transcription regulators in different combinations can control the expression of....

different

each resulting cell type would express _______ genes, as induced by their particular combination of transcription regulators

Terminally differentiated cells

cells that can only give rise to cells of their own cell type when they divide

so it can be passed on during every cell division

why must a cell remember the patterns of gene expression that led to its differentiation?

1) feedback loop circuits involving transcription regulators

2) the preservation of covalent histone modifications and chromatin condensation patterns

3) the preservation of DNA methylation patterns

The 3 mechanims of inheritance of patterns of gene expression

they involve heritable changes in gene expression that are not caused by changes in the DNA sequence

Describe why these 3 mechanisms are examples of epigenetic inheritance

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

Once a signal triggers the expression of a transcription regulator...

positive

The acetylation of the lysine tail eliminates its _______ charge

HAT

histone acetyltransferase

HDAC

histone deacetylase

positively charges lysine tails in histone proteins interact with the negative charges of the phosphate groups in DNA, strengthening the histone-DNA interactions

the neutralization of the lysine tails by acetylation weakens these interactions and allows other proteins like transcription factors to bind to DNA and stimulate transcription

How does histone acetylation stimulate transcription initiation?

1) nucleosome partially disassembles into two half-nucleosomes

2) fork replicates past hald nucleosomes

3) nucleosomes reassemble from old hald nucleosomes and newly synthesized histones

3 steps of the replication of nucleosomes

the enzyme can restore the parental patterns of histone modifications and chromatin condensation

the tissue-specific histone modifying enzyme is preserved throughout cell division and passed on to daughter cells, this way...

on cytosines that are immediately followed by guanine and only at specific sites depending on the needs of the cell related to gene expression

when and where does methylation of DNA occur?

attracting proteins that block transcription

These methylated sites turn off gene expression by...

parental

Immediately following DNA replication, only the _________ strand will have methylated cytosines

maintenance methyltransferase

the enzyme that recognizes only already methylated CG sequences, and catalyzes the methylation of the corresponding CGs in the new, complementray strand

preserved

The enzyme is ______ throughout cell division and passed on to daughter cells to preserve the same methylation pattern

de novo methyltransferase

establish new DNA methylation patterns during development, or in response to external cues such as the envrionement, behavior, or diet

DNA methyltransferase 3

the product of de novo methyltransferase which methylates and silences queen-specific genes in worker bees

royal jelly

the jelly fed to a few female larvae to ensure one becomes the queen

it silences de novo methyltransferase so the queen is less methylated

how does the royal jelly work?