or
α-ketoglutarate as cofactors) followed by the elimination of
formaldehyde. The mechanism of KDM1A and KDM1B is dependent on the formation of an iminium intermediate and therefore they may only demethylate mono- and dimethylated lysine substrates.
Histone methylation was initially considered an effectively irreversible process as the half-life of the histone methylation was approximately equal to the histone half-life. Histone lysine demethylase LSD1 (later classified as KDM1A) was first identified in 2004 as a nuclear amine oxidase homolog. Two main classes of histone lysine demethylases exist, defined by their mechanisms:
flavin adenine dinucleotide (FAD)-dependent
amine oxidases and
α-ketoglutarate-dependent hydroxylases. Histone lysine demethylases possess a variety of
domains that are responsible for histone recognition, DNA binding, methylated
amino acid substrate binding and catalytic activity. These include: • FAD-dependent amine oxidase domains containing the active catalytic site of KDM1 • Jumonji-C domains containing the active catalytic site of KDM2 through KDM8 • Jumonji-N domains responsible for Jumonji-C domain conformation stability • SWIRM (SWI3P, RSC8P and Moira) domains proposed as an anchor site for histone substrates and responsible for
chromatin stability • PHD, CXXC and C5HC2
zinc finger domains responsible for histone recognition and binding Histone lysine demethylases are classified according to their domains and unique substrate specificities. The lysine substrates and identified according to their position in the corresponding histone amino acid sequence and methylation state (for example, H3K9me3 refers to trimethylated histone 3 lysine 9.) ;
KDM1:The KDM1 homologs include
KDM1A and
KDM1B. KDM1A demethylates H3K4me1/2 and H3K9me1/2, and KDM1B emethylates H3K4me1/2. KDM1 activity is critical to
embryogenesis and tissue-specific
differentiation, as well as oocyte growth. KDM1A gene expression is observed to be upregulated in some cancers, and so KDM1A inhibition has therefore been considered a possible epigenetic treatment for cancer.:KDM1B, however, is mostly involved in
oocyte development. Deletion of this gene leads to
maternal effect lethality in mice. Orthologs of KDM1 in
D. melanogaster and
C. elegans appear to function similarly to KDM1B rather than KDM1A. ;
KDM2:The KDM2 homologs include
KDM2A and
KDM2B. KDM2A and KDM2B demethylate H3K4me3 and H3K36me2/3. KDM2A has roles in either promoting or inhibiting tumor function, and KDM2B has roles in
oncogenesis.:Overexpressed KDM2B has been observed in human
lymphoma and
adenocarcinoma, and underexpressed KDM2B has been observed in human prostate cancer and glioblastoma. KDM2B has been additionally shown to prevent
senescence in some cells through
ectopic expression. ;
KDM3:The KDM3 homologs include
KDM3A,
KDM3B and
KDM3C. KDM3A, KDM3B and KDM3C demethylate H3K9me1/2. KDM3A has roles in
spermatogenesis and metabolic functions, however, the activity of KDM3B and KDM3C are not specifically known. ;
KDM4:The KDM4 homologs include
KDM4A,
KDM4B,
KDM4C,
KDM4D, KDM4E and KDM4F. KDM4A, KDM4B and KDM4C demethylate H3K9me2/3, H3K9me3 and H3K36me2/3, and KDM4D, KDM4E and KDM4F demethylate H3K9me2/3. KDM4A, KDM4B, KDM4C and KDM4D have roles in
tumorigenesis, however, the activity of KDM4E and KDM4F are not specifically known.. Other gene expression data has also suggested KDM4A, KDM4B, and KDM4C are overexpressed in prostate cancer. ;
KDM5:The KDM5 homologs includes
KDM5A,
KDM5B,
KDM5C and
KDM5D. KDM5A, KDM5B, KDM5C and KDM5D demethylate H3K4me2/3. KDM5B and KDM5C have also shown to interaction with PcG proteins, which are involved in transcriptional repression. KDM5C mutations on the X-chromosome have also been observed in patients with
X-linked intellectual disability. Depletion of KDM5C homologs in
D. rerio have shown brain-patterning defects and neuronal cell death. ;
KDM6:The KDM6 family includes
KDM6A,
KDM6B and
KDM6C. KDM6A and KDM6B demethylate H3K27me2/3, and KDM4C demethylates H3K27me3. KDM6A and KDM6B possess tumor-suppressive characteristics. KDM6A knockdowns in
fibroblasts lead to an immediate increase in fibroblast population. KDM6B expressed in fibroblasts induces oncogenes of the Ras/Raf/MEK/ERK pathway. Point mutations of KDM6A have been identified as one cause of
Kabuki syndrome, a congenital disorder resulting in intellectual disability. Deletion of KDM6A in
D. rerio results in decreased expression of HOX genes, which play a role in regulating
body patterning during development. In mammalian studies, KDM6A has been shown to regulate HOX genes as well. Mutation of KDM5B disrupt gonad development in
C.elegans. Other studies have shown that KDM6B expression is upregulated in activated
macrophages and dynamically expressed during differentiation of
stem cells. == Ester demethylation ==