Biology:KDM4A

Short description: Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the Kdm4a gene

Generic protein structure example

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

Function

This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein with a JmjN domain, a JmjC domain, a JD2H domain, two TUDOR domains, and two PHD-type zinc fingers. This nuclear protein belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily. It functions as a trimethylation-specific demethylase, converting specific trimethylated histone on histone H3 lysine 9 and 36 residues to the dimethylated form and lysine 9 dimethylated residues to monomethyl, and as a transcriptional repressor.

Alterations in this gene have been found associated with chromosomal instability that leads to cancer.

In humans, the role of Kdm4a as an oncogene, or cancer associated gene, is well established. It is implicated in prostate tumors, where it is overexpressed, and stimulates cell proliferation in colon cancer cells, where it promotes formation of the tumor itself. In lung cancer cell lines, where Kdm4a is also overexpressed, it coordinates with other oncogenes (like Ras) to transform normal cells into cancerous cells by inhibiting tumor suppressor pathways such as p53. Suppression of Kdm4a in breast cancer cell lines has shown to reduce cancer cell proliferation through cell cycle arrest, and decrease tumor migration and invasion.

In mice models, Kdm4a influences various processes leading up to implantation of the embryo. The expression of this gene is observed in all tissues critical to the female reproductive system, including the hypothalamus, pituitary, ovary, oviducts, and uterus, as well as embryonic development. A knockout of this gene in female mice has shown to negatively interfere with maintaining a maternal uterine environment suitable to receive and implant the blastocyst. It also interferes in the early embryonic development of the female mice's pups prior to implantation, leading to infertility. While mechanisms of normal ovulation and fertilization remain unaffected, infertility may also be partly due to decreased levels of Prolactin, a hormone crucial during the process of pregnancy. A knockout of Kdm4a has no effect on the fertility or viability of male pups.

Further reading

• "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. September 1996. doi:10.1101/gr.6.9.791. PMID 8889548. 
• "N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso". Molecular Cell 12 (3): 723–34. September 2003. doi:10.1016/j.molcel.2003.08.008. PMID 14527417. 
• "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nature Biotechnology 22 (6): 707–16. June 2004. doi:10.1038/nbt971. PMID 15146197. 
• "Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions". Genome Research 14 (9): 1711–8. September 2004. doi:10.1101/gr.2435604. PMID 15342556. 
• "Functional characterization of JMJD2A, a histone deacetylase- and retinoblastoma-binding protein". The Journal of Biological Chemistry 280 (31): 28507–18. August 2005. doi:10.1074/jbc.M413687200. PMID 15927959. 
• "JMJD2A is a novel N-CoR-interacting protein and is involved in repression of the human transcription factor achaete scute-like homologue 2 (ASCL2/Hash2)". Molecular and Cellular Biology 25 (15): 6404–14. August 2005. doi:10.1128/MCB.25.15.6404-6414.2005. PMID 16024779. 
• "Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry". Nature Methods 2 (8): 591–8. August 2005. doi:10.1038/nmeth776. PMID 16094384. 
• "Tudor, MBT and chromo domains gauge the degree of lysine methylation". EMBO Reports 7 (4): 397–403. April 2006. doi:10.1038/sj.embor.7400625. PMID 16415788. 
• "Recognition of histone H3 lysine-4 methylation by the double tudor domain of JMJD2A". Science 312 (5774): 748–51. May 2006. doi:10.1126/science.1125162. PMID 16601153. Bibcode: 2006Sci...312..748H. 
• "Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases". Cell 125 (3): 467–81. May 2006. doi:10.1016/j.cell.2006.03.028. PMID 16603238. 
• "Structural insights into histone demethylation by JMJD2 family members". Cell 125 (4): 691–702. May 2006. doi:10.1016/j.cell.2006.04.024. PMID 16677698. 
• "The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36". Nature 442 (7100): 312–6. July 2006. doi:10.1038/nature04853. PMID 16732292. Bibcode: 2006Natur.442..312K. 
• "Activation of androgen receptor by histone demethylases JMJD2A and JMJD2D". Biochemical and Biophysical Research Communications 359 (3): 742–6. August 2007. doi:10.1016/j.bbrc.2007.05.179. PMID 17555712. 
• "Structural basis of the recognition of a methylated histone tail by JMJD2A". Proceedings of the National Academy of Sciences of the United States of America 104 (26): 10818–23. June 2007. doi:10.1073/pnas.0704525104. PMID 17567753. Bibcode: 2007PNAS..10410818C. 
• "Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity". Nature 448 (7149): 87–91. July 2007. doi:10.1038/nature05971. PMID 17589501. Bibcode: 2007Natur.448...87N. 
• "Distinct binding modes specify the recognition of methylated histones H3K4 and H4K20 by JMJD2A-tudor". Nature Structural & Molecular Biology 15 (1): 109–11. January 2008. doi:10.1038/nsmb1326. PMID 18084306.