Genomics and Chromosome Organization

Pseudogenes and Genome Instability

• Pseudogenes originate from genic sequences and are typically inserted into new locations via transposons.
• Repetitive sequences can cause genomic instability, leading to errors in DNA repair, which may result in inversions and deletions.
• An example of genome rearrangement is Williams Syndrome, which exhibits specific physical traits and sociable behavior.

Epigenetic Modification of Histones

• Enzymatic regulation of chromosome structure involves modifying histone N-terminal tails through acetylation, methylation, phosphorylation, and ubiquitination.
• Histone acetyl transferases (HATs) acetylate lysine side chains, reducing their positive charge. This promotes an open chromatin conformation, facilitating transcription factor access.
• Acetylation of lysines forms an amide bond, similar to peptide bonds.
• Histone deacetylases (HDACs) remove acetyl groups, leading to compact nucleosome packaging and repression of transcription.
• Histone methyltransferases (HMTs) add methyl groups to lysines, resulting in activating (e.g., H3K4me) or inhibiting (e.g., H3K9me) modifications.
• Lysines can be modified by mono-, di-, or tri-methylation, and specific enzymes demethylate these sites.
• Many HATs and HMTs must recognize their modification products, with HATs often containing bromodomains that specifically recognize acetylated histones.
• Competition exists between acetylation and methylation at specific histone positions, creating a complex regulatory landscape.
• Histone modifications can be epigenetically inherited by daughter cells, thus not being encoded in the DNA sequence.

DNA Methylation

• DNA can undergo methylation, primarily at cytosines, which is considered an epigenetic modification due to its heritable nature.
• Cytosine is often methylated at the 5' position within CpG sequences, typically clustered into "CpG islands."
• Proteins like methyl-cytosine binding protein (MeCP2) bind to methylated cytosines and recruit DNA methyltransferases (DNMT) to propagate the modification.
• DNA methylation is interrelated with histone modifications; for example, MeCP2 also recruits histone deacetylases.
• Methylation is commonly found in gene promoter regions and is associated with gene repression.
• Repetitive elements, particularly transposable elements, experience high levels of methylation, contributing to their repression.

Chromatin Compaction and Epigenetic Modifications

• Heterochromatin compaction is reliant on specific epigenetic modifications, particularly H3K9 methylation.
• H3K9me serves as a binding site for heterochromatin protein 1 (HP1), a reader protein that recruits various modifying enzymes.
• The spreading of these modifications can lead to local chromatin compaction and inactivation of adjacent genes.
• Insulators located at topologically associating domain (TAD) boundaries can suppress the lateral spread of modifications through steric disruption.
• Heterochromatin formation can be initiated by DNA binding proteins or the production of double-stranded RNA from repeats, leading to recruitment of H3K9 methylases.