H3K36me3 is an
epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
modification to the DNA packaging protein
Histone H3
Histone H3 is one of the five main histones involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'beads on a st ...
. It is a mark that indicates the tri-
methylation at the 36th
lysine residue of the histone H3 protein and often associated with
gene bodies.
There are diverse modifications at H3K36 and have many important biological processes. H3K36 has different acetylation and methylation states with no similarity to each other.
Nomenclature
H3K36me3 indicates
trimethylation of
lysine 36 on histone H3 protein subunit:
Lysine Methylation
This diagram shows the progressive methylation of a lysine residue. The tri-methylation denotes the methylation present in H3K36me3.
Understanding histone modifications
The genomic DNA of eukaryotic cells is wrapped around special protein molecules known as
Histones
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are ...
. The complexes formed by the looping of the DNA are known as
chromatin
Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...
. The basic structural unit of chromatin is the
nucleosome: this consists of the core octamer of histones (H2A, H2B, H3 and H4) as well as a linker histone and about 180 base pairs of DNA. These core histones are rich in lysine and arginine residues. The
carboxyl (C) terminal end of these histones contribute to histone-histone interactions, as well as histone-DNA interactions. The amino
(N) terminal charged tails are the site of the post-translational modifications, such as the one seen in H3K36me3.
Mechanism and function of modification
Binding proteins
H3K36me3 can bind
chromodomain
A chromodomain (''chromatin organization modifier'') is a protein structural domain of about 40–50 amino acid residues commonly found in proteins associated with the remodeling and manipulation of chromatin. The domain is highly conserved amon ...
proteins such as MSL3 hMRG15 and scEaf3.
It can bind
PWWP proteins such as BRPF1
DNMT3A,
HDGF2 and
Tudor domains such as PHF19 and PHF1.
DNA repair
H3K36me3 is required for
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
al
repair of DNA damage such as double-strand breaks.
The trimethylation is catalyzed by
SETD2 methyltransferase
Methyltransferases are a large group of enzymes that all Methylation, methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which co ...
.
Other roles
H3K36me3 acts as a mark for
HDAC
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
s to bind and deacetylate the histone which would prevent run-away transcription.
It is associated with both facultative and constitutive
heterochromatin.
Relationship with other modifications
H3K36me3 might define
exons. Nucleosomes in the exons have more histone modifications such as H3K79, H4K20, and especially H3K36me3.
Epigenetic implications
The post-translational modification of histone tails by either histone modifying complexes or chromatin remodelling complexes are interpreted by the cell and lead to complex, combinatorial transcriptional output. It is thought that a
Histone code
The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications (known as ''histone marks'') to histone proteins, primarily on their unstructured ends. Together with sim ...
dictates the expression of genes by a complex interaction between the histones in a particular region. The current understanding and interpretation of histones comes from two large scale projects:
ENCODE and the Epigenomic roadmap. The purpose of the epigenomic study was to investigate epigenetic changes across the entire genome. This led to chromatin states which define genomic regions by grouping the interactions of different proteins and/or histone modifications together.
Chromatin states were investigated in Drosophila cells by looking at the binding location of proteins in the genome. Use of
ChIP-sequencing revealed regions in the genome characterised by different banding. Different developmental stages were profiled in Drosophila as well, an emphasis was placed on histone modification relevance. A look in to the data obtained led to the definition of chromatin states based on histone modifications. Certain modifications were mapped and enrichment was seen to localize in certain genomic regions. Five core histone modifications were found with each respective one being linked to various cell functions.
*
H3K4me3-promoters
*
H3K4me1- primed enhancers
* H3K36me3-gene bodies
*
H3K27me3-polycomb repression
*
H3K9me3-heterochromatin
The human genome was annotated with chromatin states. These annotated states can be used as new ways to annotate a genome independently of the underlying genome sequence. This independence from the DNA sequence enforces the epigenetic nature of histone modifications. Chromatin states are also useful in identifying regulatory elements that have no defined sequence, such as enhancers. This additional level of annotation allows for a deeper understanding of cell specific gene regulation.
Clinical significance
This histone methylation is responsible for maintaining gene expression stability. It is important throughout aging and has an impact on longevity. Genes that change their expression during aging have much lower levels of H3K36me3 in their gene bodies.
There is reduced levels of H3K36me3 and
H3K79me2
H3K79me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 79th lysine residue of the histone H3 protein. H3K79me2 is detected in the transcribed regions of active genes.
...
at the upstream GAA region of the
FXN, indicative of a defect
of transcription elongation in
Friedreich's ataxia
Friedreich's ataxia (FRDA or FA) is an autosomal-recessive genetic disease that causes difficulty walking, a loss of sensation in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 year ...
.
Methods
The histone mark H3K36me3 can be detected in a variety of ways:
1. Chromatin Immunoprecipitation Sequencing (
ChIP-sequencing) measures the amount of DNA enrichment once bound to a targeted protein and immunoprecipitated. It results in good optimization and is used in vivo to reveal DNA-protein binding occurring in cells. ChIP-Seq can be used to identify and quantify various DNA fragments for different histone modifications along a genomic region.
2. Micrococcal Nuclease sequencing (MNase-seq) is used to investigate regions that are bound by well positioned nucleosomes. Use of the micrococcal nuclease enzyme is employed to identify nucleosome positioning. Well positioned nucleosomes are seen to have enrichment of sequences.
3. Assay for transposase accessible chromatin sequencing (ATAC-seq) is used to look in to regions that are nucleosome free (open chromatin). It uses hyperactive
Tn5 transposon
A transposase is any of a class of enzymes capable of binding to the end of a transposon and catalysing its movement to another part of a genome, typically by a cut-and-paste mechanism or a replicative mechanism, in a process known as transpositio ...
to highlight nucleosome localisation.
See also
*
Histone methylation
*
Histone methyltransferase
Histone methyltransferases (HMT) are histone-modifying enzymes (e.g., histone-lysine N-methyltransferases and histone-arginine N-methyltransferases), that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues ...
*
Methyllysine
References
{{reflist
Epigenetics
Post-translational modification