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Eukaryotic Epigenetic Gene Regulation
Eukaryotic Epigenetic Gene Regulation
Dr.V.Malathi
The DNA and histones that bind the DNA can undergo changes. These changes do not alter the nucleotide sequence and are not permanent, though they often persist through multiple rounds of cell division. These temporary changes can alter the chromosome structure as required. A gene can be turned on or off depending upon the location and modifications to the histone proteins and DNA. This type of gene regulation is called epigenetic regulation.
Role of Histones in gene regulation
•Histone/nucleosome winding of the DNA molecule may change with the gene activity in a particular cell or tissue.
•When a gene needs to be transcribed but is unavailable because of histone proximity, moving the histone from the DNA strand can free the promoter and associated regulatory sequences so that the sequences are exposed and the gene can be expressed.
•Conversely, if an active gene associated with a nucleosome must be turned off, then moving the DNA so that repressors can attach to the gene’s silencers can also be achieved by rewinding the DNA (in the next cell cycle) on the nucleosomes in a different way.
Histone Modifications
• Histone modification is a covalent post-translational modification (PTM) to histone proteins.
• N terminal tails of histone are modified by
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- methylation,
- phosphorylation,
- acetylation,
- ubiquitylation, and
- sumoylation. (small ubiquitin-related modifier (SUMO) family are conjugated to proteins to regulate such cellular processes as nuclear transport, transcription, chromosome segregation and DNA repair.)
- Histones modifications is carried out by acetyltransferases and deacetylases, methyltransferases and demethylases.
- The PTMs made to histones can impact gene expression by altering chromatin structure or recruiting histone modifiers.
Histone -Lysine acetylation
- Histone -Lysine acetylation is regulated by two enzymes:
- Histone Acetyltransferases (HATs)–use acetyl-CoA that is specifically recognized and bound by the Arg/Gln-X-X-Gly-X-Gly/Ala segment of HATs to transfer an acetyl group to the ε-amino groups on the N-terminal tails of histones .
- Histone Deacetylases (HDACs)–reverses the above modification by HATs
- Lysine acetylation causes a destabilization of the nucleosome and chromatin structure–effectively facilitating access to the DNA for various nuclear factors like the transcription complex.
- Hyperacetylated histones are regarded to be a hallmark of transcriptionally active chromatin.
- The work of HDACs increases the affinity between the nucleosome and the DNA, leading to a closed (heterochromatin-like) chromatin conformation that minimizes accessibility for the transcriptome.
Histone methylation
- This unique posttranslational modification is performed by a specific enzyme family known as the Protein Arginine N-Methyltransferases (PRMTs).
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Along with serine/threonine phosphorylation, and lysine methylation and acetylation, arginine methylation is an epigenetic histone modification that regulates gene expression as part of the histone code
Chromatin remodeling
•It is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression.
•When chromatin is tightly packed, and not actively being transcribed it is called heterochromatin.
•When chromatin is more loosely packed, and therefore accessible for transcription it is called euchromatin.
•Chromatin remodeling is highly implicated in epigenetics.
•Epigenetic modifications to histone proteins such as methylation/demethylation and acetylation/deacetylation can alter the structure of chromatin resulting in transcriptional activation or repression.
Two classes of chromatin remodeling enzymes
a) Class I : Histone modifying enzymes
- These do not alter nucleosome position
- They bring about covalent modification of histone proteins like histone tail modifications (Ac, Me, P, Ub, etc.)
- Proteins recruited by these modifications include: i)transcription factors ii)ATP-dependent nucleosomal remodeling enzymes iii)histone modifying enzymes
b) Class II : Chromatin remodeling factors
•It shifts nucleosome position with respect to DNA, exposing regulatory sequences.
•These are often referred to as Swi/Snf factors (because they were first identified as yeast mutants defective in mating type switching and in the ability to metabolize sucrose , sucrose non-fermenting).
•Chromatin remodeling factors use energy from ATP hydrolysis to rearrange the packing of nucleosomes in higher order chromatin structures.
•Remodeling improves access to DNA or histone binding sites recognized by transcriptional regulators or histone modifiers.
• Some of these bind to :
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- Activation domains and de-condense the associated chromatin.
- Repression domains and condense the associated chromatin.