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Function

Genes expression is directly related to the condensation state of the chromatin. Indeed, chromatin can be in the form of heterochromatin (condensed form of DNA) or euchromatin (relaxed form of DNA) which correspond respectively to the transcriptionally silent and active forms of DNA. Chromatin is composed of DNA wrapped around histone octamers forming nucleosomes. The histone tails residues can be acetylated, methylated or demethylated by enzymes in order to modify chromatin state and therefore gene expression. Different types of proteins involved in this process exist, such as histone acetylase (HAT), histone methylase (HMT) or histone demethylase (HDM).

Two families of histone-lysine demethylase (KDM) have been identified as follows : the flavin (FAD)-dependent lysine-specific demethylases and the Fe(II)-dependent Jumonji C (JmjC) family. JmjC is subfamily of histone demethylases which regroups several proteins containing a specific catalytic domain called Jmjc found in 2xml structure. KDM4 demethylases belong to the JmjC family and contains six members : KDM4A-F

Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C

KDM4C/JMJD2 is a protein which converts specific trimethylated histone residues to the dimethylated form. Indeed, it catalyzes the demethylation of both Lysine 9 and Lysine 36 of histone 3 (respectively H3K9me3 and H3K36me3 by hydroxylation of the lysine methyl group. This reaction leads to a dissociation of the methyl group from the lysine histone tail. KDM4C employs (OG), Fe2+ and oxygen as cosubstrates to promote its enzymatic reaction, thus the dissociation of methyl groups.

Structural highlights

2xml is a monomeric domain composed of 348 amino acids. It is made up of two chains A and B. They are asymmetric, i.e. their sequence identities are below 95%. This domain is connected by a beta-hairpin to the rest of the protein. This domain of KDM4C can bind to 5 ligands: Zn2+, Ni2+, N-Oxalylglycine (or OGA), Cl- (interaction only with chain A) and 1,2-ethanediol (or EDO; only with chain A) :

OGA: two binding sites (chains A and B).

EDO: three binding sites, only in chain A. They are linked to 2xml by hydrogen bond.

Zn2+: two binding sites (chains A and B). It makes four coordination bonds : with three cysteines and one histidine.

Ni2+ : two binding sites (chains A and B). It makes five coordination bonds : two with OGA, two with two histidine and a last one with a glutamic acid.

Cl- : one binding site, only in chain A.

2xml presents, in each of the two chains, parallel β sheets around OGA, forming an hydrophobic (mainly made of aromatic acid) pocket. OGA interacts with 2xml amino acids through hydrogen bonds and coordination bonds with Ni2+.

The sequence of the domain has been particularly preserved around OGA (when the protein is folded). Thus, the 3D structure has been very preserved as well, indicating us that the structure.

Epigenetic

Specific enzymes are directly involved in the modification of genes expression without altering the nucleotide sequence. They can modify the chromatin structure by adding (writers), reading (readers) or removing (erasers) marks : acetyl, methyl, phosphoryl groups, ubiquitin... These epigenetic marks can either make the gene sequence more or less accessible for transcription factors depending on their nature, histones and labelled amino acids. All combinations of the nature and the localization of these epigenetic marks form the histone code.

KDM4C is a histone demethylase. This newly discovered class of proteins plays a central role in the histone modifications : it removes the methyl group (which is very stable) from the epigenetically modified amino acid. Its actions has directed consequences on gene expression. By removing one methyl group from a trimethylated Lysine 9 of histone 3 (H3K9me3, KDM4C promotes the formation of euchromatin and therefore transcriptional activation. However, KDM4C indirectly condenses chromatin by removing one methyl group from a trimethylated Lysine 36 of histone 3 (H3K36) leading to the repression of target genes expression.

Disease

KDM4C, through its catalytic activity, regulates the expression of many genes, and in particular increases it when it catalyses the demethylation of H3K9-me3 (lysine 9 from trimethylated histones 3) to H3K9-me2 (lysine 9 from dimethylated histones 3). Several KDM4C target genes are involved in cell growth. For example, they influence mitogenic signalling - which promotes mitosis and cell division -, cell cycle regulation and translation. Thus, KDM4C contributes to cell growth. For example, an insufficient amount of KDM4C causes an increase in errors during chromosome segregation during mitosis, decreasing cell viability.

The average KDM4C expression levels were higher in the tumors than in normal cells. Indeed, the gene encoding this protein is also regulated. In cancer cells, this gene is overexpressed, resulting in an increase in the amount of KDM4C.

KDM4C allows the viability of cancer cell lines, particularly for breast cancer.2 In addition, KDM4C promotes the proliferation of cancer cells, their migration and their invasive capacity in the triple-negative breast cancer. KDM4C therefore allows the development but also the maintenance of cancer cell lines.

For all the implications of KDM4C in different cancers, it is one of the main targets of anti-cancer treatments.

Furthermore, it is interesting to note that it is the only member of the KDM4 subfamily that is involved during mitosis: it is therefore an even more interesting target compared to other proteins of the KDM4 family.

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