Epigenetics is the study of heritable cellular, and physiological traits by factors other than DNA sequence. Examples are simple chemical modifications, like methylation and acetylation to DNA and interacting partners. Since the basic structure of the respective nucleobase is retained, DNA methylation is not a genetic mutation but a modification. These changes are however they play a role in controlling how, where, and when certain genes are expressed.
Epigenetic alterations are reversible meaning that they can be targets for therapy.
Understanding the alterations
has the potential to explain mechanisms of aging, human development, and the origins of several health conditions, e.g. cancer, heart disease and mental illness.
Histone Modifications and their Impact
A histone modification is a covalent post-translational modification (PTM) to histone proteins. Histone modifications act in diverse biological processes such as transcriptional activation/inactivation, chromosome packaging, and DNA damage/repair.
In general histone acetylation determine the histone assembling as well as the folding and compactness of the DNA-histone interaction and therefore presenting a switch between condensed and uncondensed chromatin structure. The latter, known as euchromatin, is transcriptionally active, whereas the former, known as heterochromatin, is transcriptionally inactive.
Histone acetyltransferases (HAT) transfer an acetyl group to specific lysine residues on histones, usually residues in the N-terminal tail. Acetylated lysine side chains of histones lose their positive charge and thus the ability to form salt bridges with the negatively charged phosphate backbone of DNA. H3 and H4 histone proteins are the primary targets of HATs.
Acetylation of H3K56, H3K64 and H3K122 or H4K16
disrupts the chromatin structure and results in lightly packed euchromatin. Euchromatin participates in the active transcription of DNA. The unfolded structure allows gene regulatory proteins and RNA polymerase complexes to bind to the DNA sequence and consequently leads to an increase of gene transcription.
Histone H3K27m3 - shutting down Transcription
H3K27m3 is a deeply studied target of epigenetic researchers looking for inactive genes. Unlike other histone methylations, H3K27m3 has only one known methyltransferase: EZH2. EZH2 is responsible for the repression many genes involved in development and cell differentiation. Therefore H3K27m3 is critical for the repression of developmental genes acting in opposition to H3K4m3. When H3K27 is trimethylated, it is tightly associated with inactive gene promoters.
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The mono- and di-methylation states are less studied; however, H3K27m2 shows a similar distribution to H3K27, while H3K27m1 is associated with active promoters. H3K27 can also be target of acetylation. Lysine residues can only be methylated or acetylated, in comparison the acetylation leads to opposite effects - with active transcription and antagonism of H3K27m3 regulated genes.
Several approaches are viable to study histones, including chromatin immunoprecipitation (together with its large-scale variants ChIP-on-chip and ChIP-Seq), fluorescent in situ hybridization or bisulfite sequencing. Recently cleavage under targets and release using nuclease (CUT&RUN) gained more and more traction as a consequent improvement for ChIP based methods.
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