Epigenetic Regulation; Cell-cell and Cell-ECM Interactions
I. Epigenetic Regulation: DNA Packaging and Chromatin Modification
a. Chromatin Structure
1. Chromosomes are comprised of DNA plus proteins; together this is called
. (Fig. #1)
2. DNA is tightly wound two times around
protein octamers to form a
(Fig. #1, #2).
3. Nucleosomes form in clusters of six, called
, with each nucleosome in a solenoid
anchored to a
4. Solenoids are coiled together forming thickened loops (Fig. #3)
5. The solenoid loops are thought to be associated with, and attached to, an organizing scaffold,
which is composed of non-histone protein, primarily an enzyme,
thought to be attached to the scaffold via specialized DNA sequences, called
attachment regions (SARs.)
6. The scaffold itself, with the associated loops of packed solenoids, spirals tightly to form
the highly condensed chromosome.
b. Histone Modifications and Transcriptional Regulation
1. Core of nucleosome composed of a histone octamer, composed of 2 subunits each of
H2A, H2B, H3, and H4 (Figs. #2, #4, #5)
2. Tails of histones can be modified by acetylation, methylation, phosphorylation,
sumoylation (SUMO = small ubiquitin-related modifier proteins), and ubiquitination.
(Figs. #5, #6, #7.)
3. Modifications of histones catalyzed by specific histone modifying enzymes (Figs. #6, #7
Histone acetyltransferases (HATs): add acetyl groups to lysines
Histone deacetylases (HDACs): remove acetyl groups from lysines
Histone methyltransferases (HMTs): add methyl groups to lysines or arginines
Histone demethylases (e.g. LSD1): remove methyl groups
Histone kinases (e.g. H3K): Add phosphate groups to serines
Remove phosphate groups
3. Histone modification and transcriptional regulation
i. Histone modifications affect packaging of DNA; may act directly by changing
conformation of histone or by acting as "marks" that recruit other factors that modify
nucleosomes and DNA packaging with histones.
ii. Packaging of DNA affects access of transcription factors and associated proteins to
promoter elements and enhancer sequences and therefore may affect which genes are
"available" for transcription.
Transcription of a whole group of genes may be
affected by local histone modifications.