Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

in humans that is encoded by the KDM1A

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. LSD1 is a flavin-dependent

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The firs ...

, which can demethylate mono- and di-methylated

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated − ...

s, specifically

histone 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 a ...

3, lysines 4 and 9 (H3K4 and H3K9). This enzyme can have roles critical in

embryogenesis An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

and tissue-specific differentiation, as well as oocyte growth. KDM1A was the first histone demethylase to be discovered though more than 30 have been described.

Structure

This gene encodes a nuclear protein containing a SWIRM domain, a FAD-binding motif, and an

amine oxidase An amine oxidase is an enzyme that catalyzes the oxidative cleavage of alkylamines into aldehydes and ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictoge ...

domain. This protein is a component of several

histone deacetylase 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 hi ...

complexes, though it silences genes by functioning as a histone demethylase.

Function

LSD1 (lysine-specific demethylase 1), also known as KDM1, is the first of several protein

demethylases discovered. Through a FAD-dependent oxidative reaction, LSD1 specifically removes histone H3K4me2 to

H3K4me1 H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers. Nomenclature H3K4me1 i ...

or H3K4me0. When forming a complex with

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in ...

(and possibly other

nuclear hormone receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...

s), LSD1 changes its substrates to H3K9me2. It's now known LSD1 complex mediates a coordinated

modification switch through enzymatic activities as well as histone modification readers in the complex. Function of KDM1A gene can be effectively examined by siRNA knockdown based on an independent validation.

Interactions

KDM1A has many different binding partners, which may be necessary for its demethylation activity. In acute myeloid leukemia (AML), GFI1B was definitively demonstrated to maintain an interaction with KDM1A that is necessary for the proliferation of the disease. Evidence for the role of KDM1A interactions with nuclear GSK3β in promoting the progression of certain cancers is also present. High levels of nuclear GSK3β were found to promote the binding of KDM1A to the deubiquitinase, USP22, which prevent the breakdown of KDM1A and cause it to accumulate in higher levels. The accumulation of KDM1A has been correlated with tumor progression in certain cancers, including

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...

, leukemia, and osteosarcoma.

Clinical significance

KDM1A appears to play an important role in the

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 ...

"reprogramming" that occurs when sperm and egg come together to make a zygote. Deletion of the gene for KDM1A can have effects on the growth and differentiation of

embryonic stem cell Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist ...

s. Deletion in mouse embryos is lethal; embryos do not progress beyond Day 7.5. KDM1A is also thought to play a role in cancer, as poorer outcomes can be correlated with higher expression of this gene. Therefore, the inhibition of KDM1A may be a possible treatment for cancer. KDM1A tends to be overexpressed in the tumor cells of certain cancers such as bladder, lung, and colorectal cancers. The specificity of KDM1A overexpression in these cancers creates the potential for targeted molecular therapy treatments, through the use of KDM1A-specific siRNAs.

Mutations

De novo mutations to KDM1A have been reported in three patients, each with developmental delays believed to be attributable in part to the mutations. All documented mutations are missense substitutions. One of the affected families has created a public website in order to identify further cases.

References

External links

* * {{NLM content