KDM1A

Last updated
KDM1A
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases KDM1A , AOF2, BHC110, KDM1, LSD1, CPRF, lysine demethylase 1A
External IDs OMIM: 609132 MGI: 1196256 HomoloGene: 32240 GeneCards: KDM1A
Orthologs
SpeciesHumanMouse
Entrez

23028

99982

Ensembl

ENSG00000004487

ENSMUSG00000036940

UniProt

O60341

Q6ZQ88

RefSeq (mRNA)

NM_001009999
NM_015013
NM_001363654

NM_133872
NM_001347221
NM_001356567

RefSeq (protein)

NP_001009999
NP_055828
NP_001350583

NP_001334150
NP_598633
NP_001343496

Location (UCSC) Chr 1: 23.02 – 23.08 Mb Chr 4: 136.28 – 136.33 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein that in humans is encoded by the KDM1A gene. [5] LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysine 4 (H3K4). Other reported methylated lysine substrates such as histone H3K9 and TP53 have not been biochemically validated. [6] This enzyme plays a critical role in oocyte growth, embryogenesis, hematopoiesis and tissue-specific differentiation. [7] LSD1 was the first histone demethylase to be discovered though more than 30 have since been described. [8]

Structure

This gene encodes a nuclear protein containing a SWIRM domain, a FAD-binding motif, and an amine oxidase domain. This protein is a component of several complexes that include histone deacetylase and DNA methytransferase 1, all of which are associated with the repression of gene transcription. It is now known the LSD1 complex mediates a coordinated histone modification switch through these various enzymatic activities which in turn are recognized by histone "readers". The methylation of histone H3 at K4 can affect both the transcription of DNA and its replication.

Mechanism of Catalysis and Protein Function

LSD1 (lysine-specific demethylase 1), through a FAD-dependent oxidative reaction, specifically removes histone H3K4me2 to H3K4me1 or H3K4me0, but not H3K4me3.

The first step of the LSD1 catalytic reaction is the abstraction of hydride from the methyl of the H3K4 side chain N-methyl by FAD in the oxidized state that generates a stabilized methylene iminium ion. This is then hydrolyzed by a water molecule to give an unstable vicinal terminal hydroxyl amine that rapidly decomposes to yield the de-methylated lysine H3K4 molecule and formaldehyde. FAD is the reduced state reacts with molecular oxygen forming a covalent mono-hydroperoxide adduct which is then hydrolyzed by water to yield hydrogen peroxide regenerating the more stable FAD oxidized (resting) state. A highly conserved lysine (Lys661 in LSD1) at the active site in FAD-dependent amine oxidases is believed to assist in this reaction. The overall reaction stoichiometry thus involves the conversion of an N-methyl group by water and oxygen to give molecules of formaldehyde, hydrogen peroxide, and the product N-H terminus.

LSD1 cannot demethylate H3K4 trimethyl (N-tri-methyl-lysine) because the initial iminium species cannot be formed owing to a lack of an available lone electron pair at the N-center, essential for formation of the requisite stabilizing pi-system.

Given this mechanism, the mutant LSD1 with the Lys661Ala substitution is unlikely to adversely impact the interaction of LSD1 with various substrates, but rather leads to less efficient flavin recycling, which presumably then proceeds at the whim of any available non-specifically bound substitute water around that face of the FAD binding site. Thus, a mutation affecting K661 does retain some demethylase activity.

Even the structures of LSD1 at a 5 Å resolution clearly show how wide-ranging the protein-protein interactions are spread over the LSD1 Tower and SWIRN regions.

One method to examine the function of the LSD1 protein is to reduced the KDM1A mRNA using a specific silencing RNA, so called siRNA knockdown. [9] By this method, the loss of function shows a dependence of both hematopoietic stem and progenitor cells on LSD1 for self-renewal and maturation to fully differentiated blood cells. The interaction of LSD1 with the transcription factor GFI1B is particularly important for regulating the balance in stem cells between replication and self-renewal as well as the maturation the megakaryocyte-erythroid progenitors to megakaryocytes.

A complementary method to the "knockdown" method is pharmacologic inhibition of LSD1; many such inhibitors such as bomedemstat do not abrogate the scaffold function of LSD1 but rather inhibit the enzymatic activity as well as the ability of the LSD1 complex to bind transcription factors in the SNAIL family, most specifically GFI1 and GFI1B. Thus, these pharmacologic inhibitors have their greatest clinical utility in the treatment of hematologic diseases in which disruption of the LSD1-GFI1B or LSD1-GFI1 interaction is the therapeutic thesis for treatment.

Interactions

LSD1 has many different protein binding partners in a cell- and developmentally-specific manner. Both its enzymatic activity and function as a scaffold are important depending on the cellular context. Indeed, in acute myeloid leukemia (AML), the interaction of LSD1 and GFI1B was definitively demonstrated to be necessary for the proliferation of leukemic initiating cells, while the LSD1 demethylase activity was not essential for this phenotype. [10]

LSD1 can be a subunit of the NuRD complex and, and as such, participates in the gene expression programs associated with metastasis in breast cancer. [11] There is also evidence that the interaction of LSD1 with nuclear GSK3β facilitates progression of certain cancers. High levels of nuclear GSK3β were found to promote the binding of LSD1 to the deubiquitinase, USP22, which prevented the degradation of LSD1 allowing LSD1 to accumulate to high levels. The accumulation of LSD1 has been correlated with tumor progression in certain cancers, including glioblastoma, leukemia, and osteosarcoma. [12]

Role in development

LSD1 appears to play an important role in the epigenetic "reprogramming" that occurs when sperm and egg unite to form the zygote. [13] [14] Deletion of KDM1A impairs the growth and differentiation of embryonic stem cells. [15] Deletion of the mouse ortholog, Kdm1a, has an embryonic lethal phenotype; embryos do not progress beyond gestational Day 7.5. [16] [17]

Clinical significance

As mentioned above, in several cancers, higher levels of expression of LSD1 are correlated with poorer outcomes suggesting LSD1 inhibition could be a part of an anti-neoplastic regimen. [18] [19] KDM1A has been found to be overexpressed in bladder, lung, and colorectal cancers. [20] Inhibitors of LSD1 are being clinically tested for the treatment of extensive-disease small cell lung cancer, castrate-resistant prostate cancer, and acute meyloid leukemia. [21] [22] Catalytic inhibitors of LSD1 such as bomedemstat, iadademstat, phenelzine, pulrodemstat, seclidemstat, and tranylcypromine are in clinical development for the treatment of hematologic malignancies including acute meyloid leukemeia and, for bomedemstat, the myeloproliferative neoplasms. [21] Given LSD1 is critical for the maturation of megakaryocytes, the bone marrow cells that produce platelets, LSD1 is well-suited as a target for the treatment of essential thrombocythemia, an indication currently in development for bomedemstat by Imago BioSciences. Inc.

Mutations

De novo mutations in KDM1A have been reported in three patients with developmental delays complementing reports that loss-of-function mutations in SETD1A, a histone H3K4 methyltransferase, contributes to the risk of schizophrenia. [23] [24] All documented mutations are missense substitutions. [25] [26] [27] LSD1 is rarely found to be mutated in cancer.

See also

Related Research Articles

<span class="mw-page-title-main">Histone deacetylase</span> Class of enzymes important in regulating DNA transcription

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code. Histones associate with DNA to form nucleosomes, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible N-terminus that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlate well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. For details of gene expression regulation by histone modifications see table below.

Demethylases are enzymes that remove methyl (CH3) groups from nucleic acids, proteins (particularly histones), and other molecules. Demethylases are important epigenetic proteins, as they are responsible for transcriptional regulation of the genome by controlling the methylation of DNA and histones, and by extension, the chromatin state at specific gene loci.

<span class="mw-page-title-main">PHD finger</span>

The PHD finger was discovered in 1993 as a Cys4-His-Cys3 motif in the plant homeodomain proteins HAT3.1 in Arabidopsis and maize ZmHox1a. The PHD zinc finger motif resembles the metal binding RING domain (Cys3-His-Cys4) and FYVE domain. It occurs as a single finger, but often in clusters of two or three, and it also occurs together with other domains, such as the chromodomain and the bromodomain.

<span class="mw-page-title-main">Histone-modifying enzymes</span> Type of enzymes

Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">EZH2</span> Protein-coding gene in the species Homo sapiens

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

<span class="mw-page-title-main">KMT2A</span> Protein-coding gene in the species Homo sapiens

Histone-lysine N-methyltransferase 2A, also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia1 (MLL1), or zinc finger protein HRX (HRX), is an enzyme that in humans is encoded by the KMT2A gene.

<span class="mw-page-title-main">KDM5A</span> Protein-coding gene in the species Homo sapiens

Lysine-specific demethylase 5A is an enzyme that in humans is encoded by the KDM5A gene.

<span class="mw-page-title-main">KDM4A</span> Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the Kdm4a gene

Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the KDM4A gene.

<span class="mw-page-title-main">KDM5C</span> Protein-coding gene in the species Homo sapiens

Lysine-specific demethylase 5C is an enzyme that in humans is encoded by the KDM5C gene. KDM5C belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily.

<span class="mw-page-title-main">KMT2D</span> Protein-coding gene in humans

Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase. It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A, KMT2B, KMT2C, KMT2F, and KMT2G.

<span class="mw-page-title-main">JARID1B</span> Protein-coding gene in the species Homo sapiens

Lysine-specific demethylase 5B also known as histone demethylase JARID1B is a demethylase enzyme that in humans is encoded by the KDM5B gene. JARID1B belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily.

<span class="mw-page-title-main">KDM4C</span> Protein-coding gene in the species Homo sapiens

Lysine-specific demethylase 4C is an enzyme that in humans is encoded by the KDM4C gene.

miR-137

In molecular biology, miR-137 is a short non-coding RNA molecule that functions to regulate the expression levels of other genes by various mechanisms. miR-137 is located on human chromosome 1p22 and has been implicated to act as a tumor suppressor in several cancer types including colorectal cancer, squamous cell carcinoma and melanoma via cell cycle control.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

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.

<span class="mw-page-title-main">Bomedemstat</span> Chemical compound

Bomedmestat is an investigational drug under development by Imago BioSciences for the treatment of myeloproliferative neoplasms including essential thrombocythemia, polycythemia vera and myelofibrosis.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000004487 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000036940 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: Lysine (K)-specific demethylase 1A".
  6. ↑ Rudolph T, Beuch S, Reuter G (August 2013). "Lysine-specific histone demethylase LSD1 and the dynamic control of chromatin". (review). Biological Chemistry. 394 (8): 1019–1028. doi:10.1515/hsz-2013-0119. PMID   23612539. S2CID   41459906.
  7. ↑ Pedersen MT, Helin K (November 2010). "Histone demethylases in development and disease". (review). Trends in Cell Biology. 20 (11): 662–671. doi:10.1016/j.tcb.2010.08.011. PMID   20863703.
  8. ↑ Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, et al. (December 2004). "Histone demethylation mediated by the nuclear amine oxidase homolog LSD1". Cell. 119 (7): 941–953. doi: 10.1016/j.cell.2004.12.012 . PMID   15620353. S2CID   10847230.
  9. ↑ Munkácsy G, Sztupinszki Z, Herman P, Bán B, Pénzváltó Z, Szarvas N, Győrffy B (September 2016). "Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments". Molecular Therapy. Nucleic Acids. 5 (9): e366. doi:10.1038/mtna.2016.66. PMC   5056990 . PMID   27673562.
  10. ↑ Vinyard ME, Su C, Siegenfeld AP, Waterbury AL, Freedy AM, Gosavi PM, et al. (May 2019). "CRISPR-suppressor scanning reveals a nonenzymatic role of LSD1 in AML". Nature Chemical Biology. 15 (5): 529–539. doi:10.1038/s41589-019-0263-0. PMC   7679026 . PMID   30992567.
  11. ↑ Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W, et al. (August 2009). "LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer". Cell. 138 (4): 660–672. doi: 10.1016/j.cell.2009.05.050 . PMID   19703393.
  12. ↑ Zhou A, Lin K, Zhang S, Chen Y, Zhang N, Xue J, et al. (September 2016). "Nuclear GSK3β promotes tumorigenesis by phosphorylating LSD1 and inducing its deubiquitylation by USP22". Nature Cell Biology. 18 (9): 954–966. doi:10.1038/ncb3396. PMC   5026327 . PMID   27501329.
  13. ↑ Ancelin K, Syx L, Borensztein M, Ranisavljevic N, Vassilev I, Briseño-Roa L, et al. (February 2016). "Maternal LSD1 is an essential regulator of chromatin and transcription landscapes during zygotic genome activation". eLife. 5. doi: 10.7554/eLife.08851 . PMC   4829419 . PMID   26836306.
  14. ↑ "Disruptions to embryonic reprogramming alter adult mouse behavior". phys.org. Retrieved 2016-06-01.
  15. ↑ Amente S, Lania L, Majello B (October 2013). "The histone LSD1 demethylase in stemness and cancer transcription programs". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1829 (10): 981–986. doi: 10.1016/j.bbagrm.2013.05.002 . PMID   23684752.
  16. ↑ Wang J, Hevi S, Kurash JK, Lei H, Gay F, Bajko J, et al. (January 2009). "The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation". Nature Genetics. 41 (1): 125–129. doi:10.1038/ng.268. PMID   19098913. S2CID   2010695.
  17. ↑ Wang J, Scully K, Zhu X, Cai L, Zhang J, Prefontaine GG, et al. (April 2007). "Opposing LSD1 complexes function in developmental gene activation and repression programmes". Nature. 446 (7138): 882–887. Bibcode:2007Natur.446..882W. doi:10.1038/nature05671. PMID   17392792. S2CID   4387240.
  18. ↑ Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R, et al. (December 2006). "Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence". Cancer Research. 66 (23): 11341–11347. doi: 10.1158/0008-5472.CAN-06-1570 . PMID   17145880.
  19. ↑ Lim S, Janzer A, Becker A, Zimmer A, Schüle R, Buettner R, Kirfel J (March 2010). "Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive tumor behavior". Carcinogenesis. 31 (3): 512–520. doi: 10.1093/carcin/bgp324 . PMID   20042638.
  20. ↑ Hayami S, Kelly JD, Cho HS, Yoshimatsu M, Unoki M, Tsunoda T, et al. (February 2011). "Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers". International Journal of Cancer. 128 (3): 574–586. doi: 10.1002/ijc.25349 . PMID   20333681. S2CID   26990673.
  21. 1 2 Noce B, Di Bello E, Fioravanti R, Mai A (2023). "LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials". (review). Frontiers in Pharmacology. 14: 1120911. doi: 10.3389/fphar.2023.1120911 . PMC   9932783 . PMID   36817147.
  22. ↑ Zhang C, Wang Z, Shi Y, Yu B, Song Y (May 2023). "Recent advances of LSD1/KDM1A inhibitors for disease therapy". (review). Bioorganic Chemistry. 134: 106443. doi:10.1016/j.bioorg.2023.106443. PMID   36857932. S2CID   257215939.
  23. ↑ Aleccia JN (7 May 2016). "Needle in the genetic haystack: How a new UW website is helping families, scientists". The Seattle Times. Retrieved 27 May 2016.
  24. ↑ Snow K (31 May 2016). "Stirrings of Hope for Families Isolated by Rarest of Genetic Conditions". KQED Future of You. Retrieved 2016-06-01.
  25. ↑ Tunovic S, Barkovich J, Sherr EH, Slavotinek AM (July 2014). "De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome". American Journal of Medical Genetics. Part A. 164A (7): 1744–1749. doi:10.1002/ajmg.a.36450. PMID   24838796. S2CID   24307221.
  26. ↑ Chong JX, Yu JH, Lorentzen P, Park KM, Jamal SM, Tabor HK, et al. (August 2016). "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features". Genetics in Medicine. 18 (8): 788–795. doi:10.1038/gim.2015.161. PMC   4902791 . PMID   26656649.
  27. ↑ Pilotto S, Speranzini V, Marabelli C, Rusconi F, Toffolo E, Grillo B, et al. (June 2016). "LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors". Human Molecular Genetics. 25 (12): 2578–2587. doi: 10.1093/hmg/ddw120 . hdl: 2434/425127 . PMID   27094131.

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