ASH1L
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ASH1L (also called huASH1, ASH1, ASH1L1, ASH1-like, or KMT2H) is a histone-lysine N-methyltransferase enzyme encoded by the ASH1L gene located at chromosomal band 1q22. ASH1L is the human homolog of Drosophila Ash1 (absent, small, or homeotic-like).
Gene
Ash1 was discovered as a gene causing an imaginal disc mutant phenotype in Drosophila. Ash1 is a member of the trithorax-group (trxG) of proteins, a group of transcriptional activators that are involved in regulating Hox gene expression and body segment identity.[3] Drosophila Ash1 interacts with trithorax to regulate ultrabithorax expression.[4]
The human ASH1L gene spans 227.5 kb on chromosome 1, band q22. This region is rearranged in a variety of human cancers such as leukemia, non-Hodgkin’s lymphoma, and some solid tumors. The gene is expressed in multiple tissues, with highest levels in brain, kidney, and heart, as a 10.5-kb mRNA transcript.[5]
Structure
Human ASH1L protein is 2969 amino acids long with a molecular weight of 333 kDa.[6] ASH1L has an associated with SET domain (AWS), a SET domain, a post-set domain, a bromodomain, a bromo-adjacent homology domain, and a plant homeodomain finger. Human and Drosophila Ash1 share 66% and 77% similarity in their SET and PHD finger domains, respectively.[5] A bromodomain is not present in Drosophila Ash1.
The SET domain is responsible for ASH1L’s histone methyltransferase (HMTase) activity. Unlike other proteins that contain a SET domain at their C terminus, ASH1L has a SET domain in the middle of the protein. The crystal structure of the human ASH1L catalytic domain, including the AWS, SET, and post-SET domains, has been solved to 2.9 angstrom resolution. The structure shows that the substrate binding pocket is blocked by a loop from the post-SET domain, and because mutation of the loop stimulates ASH1L HMTase activity, it was proposed that this loop serves a regulatory role.[7]
Function
The ASH1L protein is localized to intranuclear speckles and tight junctions, where it was hypothesized to function in adhesion-mediated signaling.[5] ChIP analysis demonstrated that ASH1L binds to the 5’-transcribed region of actively transcribed genes. The chromatin occupancy of ASH1L mirrors that of the TrxG-related H3K4-HMTase MLL1, however ASH1L’s association with chromatin can occur independently of MLL1. While ASH1L binds to the 5’-transcribed region of housekeeping genes, it is distributed across the entire transcribed region of Hox genes. ASH1L is required for maximal expression and H3K4 methylation of HOXA6 and HOXA10.[8]
A Hox promoter reporter construct in HeLa cells requires both MLL1 and ASH1L for activation, whereas MLL1 or ASH1L alone are not sufficient to activate transcription. Interestingly, the methyltransferase activity of ASH1L is not required for Hox gene activation but instead has repressive action. Knockdown of ASH1L in K562 cells causes up-regulation of the ε-globin gene and down-regulation of myelomoncytic markers GPIIb and GPIIIa, and knockdown of ASH1L in lineage marker-negative hematopoietic progenitor cells skews differentiation from myelomonocytic towards lymphoid or erythroid lineages. These results imply that ASH1L, like MLL1, facilitates myelomonocytic differentiation of hematopoietic stem cells.[3]
The in vivo target for ASH1L’s HMTase activity has been a topic of some controversy. Blobel’s group found that in vitro ASH1L methylates H3K4 peptides, and the distribution of ASH1L across transcribed genes resembles that of H3K4 levels.[8] In contrast, two other groups have found that ASH1L’s HMTase activity is directed toward H3K36, using nucleosomes as substrate.[7][9]
Role in Disease
ASH1L has been implicated in facioscapulohumeral muscular dystrophy, a common autosomal-dominant myopathy in which patients experience progressive muscle wasting in the face, upper arm, and shoulder muscles. At the molecular level, FSHD is associated with a lower-than-normal number of D4Z4 repeats at 4q35. D4Z4 copy number reduction in FSHD patients causes insufficient binding of Polycomb-group repressors, permitting transcription of a long noncoding RNA called DBE-T that is encoded by a sequence within D4Z4 repeats. DBE-T recruits ASH1L to the FSHD locus, resulting in H3K36 dimethylation, chromatin remodeling, and 4q35 gene de-repression.[10]
References
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- 1 2 Tanaka Y, Kawahashi K, Katagiri Z, Nakayama Y, Mahajan M, Kioussis D (2011). "Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression". PLoS ONE. 6 (11): e28171. doi:10.1371/journal.pone.0028171. PMC 3225378
. PMID 22140534. - ↑ Rozovskaia T, Tillib S, Smith S, Sedkov Y, Rozenblatt-Rosen O, Petruk S, Yano T, Nakamura T, Ben-Simchon L, Gildea J, Croce CM, Shearn A, Canaani E, Mazo A (1999). "Trithorax and ASH1 interact directly and associate with the trithorax group-responsive bxd region of the Ultrabithorax promoter". Mol. Cell. Biol. 19 (9): 6441–7. PMC 84613. PMID 10454589.
- 1 2 3 Nakamura T, Blechman J, Tada S, Rozovskaia T, Itoyama T, Bullrich F, Mazo A, Croce CM, Geiger B, Canaani E (2000). "huASH1 protein, a putative transcription factor encoded by a human homologue of the Drosophila ash1 gene, localizes to both nuclei and cell-cell tight junctions". Proc. Natl. Acad. Sci. U.S.A. 97 (13): 7284–9. doi:10.1073/pnas.97.13.7284. PMC 16537. PMID 10860993.
- ↑ "ASH1L_HUMAN". UniProt. Retrieved 24 August 2012.
- 1 2 An S, Yeo KJ, Jeon YH, Song JJ (2011). "Crystal structure of the human histone methyltransferase ASH1L catalytic domain and its implications for the regulatory mechanism". J. Biol. Chem. 286 (10): 8369–74. doi:10.1074/jbc.M110.203380. PMC 3048721. PMID 21239497.
- 1 2 Gregory GD, Vakoc CR, Rozovskaia T, Zheng X, Patel S, Nakamura T, Canaani E, Blobel GA (2007). "Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes". Mol. Cell. Biol. 27 (24): 8466–79. doi:10.1128/MCB.00993-07. PMC 2169421. PMID 17923682.
- ↑ Tanaka Y, Katagiri Z, Kawahashi K, Kioussis D, Kitajima S (2007). "Trithorax-group protein ASH1 methylates histone H3 lysine 36". Gene. 397 (1-2): 161–8. doi:10.1016/j.gene.2007.04.027. PMID 17544230.
- ↑ Cabianca DS, Casa V, Bodega B, Xynos A, Ginelli E, Tanaka Y, Gabellini D (2012). "A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy". Cell. 149 (4): 819–31. doi:10.1016/j.cell.2012.03.035. PMC 3350859. PMID 22541069.
Further reading
- Nagase T, Kikuno R, Ishikawa KI, et al. (2000). "Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro.". DNA Res. 7 (1): 65–73. doi:10.1093/dnares/7.1.65. PMID 10718198.
- Brandenberger R, Wei H, Zhang S, et al. (2005). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation.". Nat. Biotechnol. 22 (6): 707–16. doi:10.1038/nbt971. PMID 15146197.
- Colland F, Jacq X, Trouplin V, et al. (2004). "Functional proteomics mapping of a human signaling pathway.". Genome Res. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
- Kimura K, Wakamatsu A, Suzuki Y, et al. (2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
- Vasilescu J, Zweitzig DR, Denis NJ, et al. (2007). "The proteomic reactor facilitates the analysis of affinity-purified proteins by mass spectrometry: application for identifying ubiquitinated proteins in human cells.". J. Proteome Res. 6 (1): 298–305. doi:10.1021/pr060438j. PMID 17203973.