ASH1L

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.{{cite journal | vauthors = Tanaka Y, Kawahashi K, Katagiri Z, Nakayama Y, Mahajan M, Kioussis D | title = Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression | journal = PLOS ONE | volume = 6 | issue = 11 | pages = e28171 | year = 2011 | pmid = 22140534 | pmc = 3225378 | doi = 10.1371/journal.pone.0028171 | doi-access = free | bibcode = 2011PLoSO...628171T }} Drosophila Ash1 interacts with trithorax to regulate ultrabithorax expression.{{cite journal | vauthors = 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 | display-authors = 6 | title = Trithorax and ASH1 interact directly and associate with the trithorax group-responsive bxd region of the Ultrabithorax promoter | journal = Molecular and Cellular Biology | volume = 19 | issue = 9 | pages = 6441–6447 | date = September 1999 | pmid = 10454589 | pmc = 84613 | doi = 10.1128/MCB.19.9.6441 }}

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.{{cite journal | vauthors = Nakamura T, Blechman J, Tada S, Rozovskaia T, Itoyama T, Bullrich F, Mazo A, Croce CM, Geiger B, Canaani E | display-authors = 6 | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 13 | pages = 7284–7289 | date = June 2000 | pmid = 10860993 | pmc = 16537 | doi = 10.1073/pnas.97.13.7284 | doi-access = free | bibcode = 2000PNAS...97.7284N }} Mutations in ASH1L in humans have been associated with autism, epilepsy, and intellectual disability.

Structure

Human ASH1L protein is 2969 amino acids long with a molecular weight of 333 kDa.{{cite web|title=ASH1L_HUMAN|url=https://www.uniprot.org/uniprot/Q9NR48|work=UniProt|access-date=24 August 2012}} 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 (PHD finger). Human and Drosophila Ash1 share 66% and 77% similarity in their SET and PHD finger domains, respectively. 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.{{cite journal | vauthors = An S, Yeo KJ, Jeon YH, Song JJ | title = Crystal structure of the human histone methyltransferase ASH1L catalytic domain and its implications for the regulatory mechanism | journal = The Journal of Biological Chemistry | volume = 286 | issue = 10 | pages = 8369–8374 | date = March 2011 | pmid = 21239497 | pmc = 3048721 | doi = 10.1074/jbc.M110.203380 | doi-access = free }}

Protein expression patterns and timing

ASH1L is ubiquitously expressed throughout the body.{{Cite web |title=ASH1L protein expression summary - The Human Protein Atlas |url=https://www.proteinatlas.org/ENSG00000116539-ASH1L. |access-date=2024-02-15 |website=www.proteinatlas.org}}{{cite journal | vauthors = Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Pontén F | display-authors = 6 | title = Proteomics. Tissue-based map of the human proteome | journal = Science | volume = 347 | issue = 6220 | pages = 1260419 | date = January 2015 | pmid = 25613900 | doi = 10.1126/science.1260419 }}{{cite journal | vauthors = Smith CM, Hayamizu TF, Finger JH, Bello SM, McCright IJ, Xu J, Baldarelli RM, Beal JS, Campbell J, Corbani LE, Frost PJ, Lewis JR, Giannatto SC, Miers D, Shaw DR, Kadin JA, Richardson JE, Smith CL, Ringwald M | display-authors = 6 | title = The mouse Gene Expression Database (GXD): 2019 update | journal = Nucleic Acids Research | volume = 47 | issue = D1 | pages = D774–D779 | date = January 2019 | pmid = 30335138 | pmc = 6324054 | doi = 10.1093/nar/gky922 }}{{cite journal | vauthors = Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlén M | display-authors = 6 | title = Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics | journal = Molecular & Cellular Proteomics | volume = 13 | issue = 2 | pages = 397–406 | date = February 2014 | pmid = 24309898 | doi = 10.1074/mcp.m113.035600 | doi-access = free | pmc = 3916642 }} In the brain, ASH1L is expressed across brain areas and cell types, including excitatory and inhibitory neurons, astrocytes, oligodendrocytes, and microglia.{{cite journal | vauthors = Tasic B, Yao Z, Graybuck LT, Smith KA, Nguyen TN, Bertagnolli D, Goldy J, Garren E, Economo MN, Viswanathan S, Penn O, Bakken T, Menon V, Miller J, Fong O, Hirokawa KE, Lathia K, Rimorin C, Tieu M, Larsen R, Casper T, Barkan E, Kroll M, Parry S, Shapovalova NV, Hirschstein D, Pendergraft J, Sullivan HA, Kim TK, Szafer A, Dee N, Groblewski P, Wickersham I, Cetin A, Harris JA, Levi BP, Sunkin SM, Madisen L, Daigle TL, Looger L, Bernard A, Phillips J, Lein E, Hawrylycz M, Svoboda K, Jones AR, Koch C, Zeng H | display-authors = 6 | title = Shared and distinct transcriptomic cell types across neocortical areas | journal = Nature | volume = 563 | issue = 7729 | pages = 72–78 | date = November 2018 | pmid = 30382198 | pmc = 6456269 | doi = 10.1038/s41586-018-0654-5 | bibcode = 2018Natur.563...72T }}{{cite journal | vauthors = Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, Vogel H, Steinberg GK, Edwards MS, Li G, Duncan JA, Cheshier SH, Shuer LM, Chang EF, Grant GA, Gephart MG, Barres BA | display-authors = 6 | title = Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse | journal = Neuron | volume = 89 | issue = 1 | pages = 37–53 | date = January 2016 | pmid = 26687838 | pmc = 4707064 | doi = 10.1016/j.neuron.2015.11.013 }}{{cite journal | vauthors = Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ | display-authors = 6 | title = An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex | journal = The Journal of Neuroscience | volume = 34 | issue = 36 | pages = 11929–11947 | date = September 2014 | pmid = 25186741 | pmc = 4152602 | doi = 10.1523/JNEUROSCI.1860-14.2014 }} ASH1L also does not appear to show specificity to any brain region. In humans, ASH1L mRNA expression levels are fairly equal across all regions of cortex.{{cite journal | vauthors = Miller JA, Ding SL, Sunkin SM, Smith KA, Ng L, Szafer A, Ebbert A, Riley ZL, Royall JJ, Aiona K, Arnold JM, Bennet C, Bertagnolli D, Brouner K, Butler S, Caldejon S, Carey A, Cuhaciyan C, Dalley RA, Dee N, Dolbeare TA, Facer BA, Feng D, Fliss TP, Gee G, Goldy J, Gourley L, Gregor BW, Gu G, Howard RE, Jochim JM, Kuan CL, Lau C, Lee CK, Lee F, Lemon TA, Lesnar P, McMurray B, Mastan N, Mosqueda N, Naluai-Cecchini T, Ngo NK, Nyhus J, Oldre A, Olson E, Parente J, Parker PD, Parry SE, Stevens A, Pletikos M, Reding M, Roll K, Sandman D, Sarreal M, Shapouri S, Shapovalova NV, Shen EH, Sjoquist N, Slaughterbeck CR, Smith M, Sodt AJ, Williams D, Zöllei L, Fischl B, Gerstein MB, Geschwind DH, Glass IA, Hawrylycz MJ, Hevner RF, Huang H, Jones AR, Knowles JA, Levitt P, Phillips JW, Sestan N, Wohnoutka P, Dang C, Bernard A, Hohmann JG, Lein ES | display-authors = 6 | title = Transcriptional landscape of the prenatal human brain | journal = Nature | volume = 508 | issue = 7495 | pages = 199–206 | date = April 2014 | pmid = 24695229 | pmc = 4105188 | doi = 10.1038/nature13185 | bibcode = 2014Natur.508..199M }}{{cite journal | vauthors = Cheon S, Culver AM, Bagnell AM, Ritchie FD, Vacharasin JM, McCord MM, Papendorp CM, Chukwurah E, Smith AJ, Cowen MH, Moreland TA, Ghate PS, Davis SW, Liu JS, Lizarraga SB | display-authors = 6 | title = Counteracting epigenetic mechanisms regulate the structural development of neuronal circuitry in human neurons | journal = Molecular Psychiatry | volume = 27 | issue = 4 | pages = 2291–2303 | date = April 2022 | pmid = 35210569 | pmc = 9133078 | doi = 10.1038/s41380-022-01474-1 }} Similarly, in mice, ASH1L protein is highly expressed in the hippocampus, thalamus, hypothalamus, motor cortex, and basolateral amygdala.{{cite journal | vauthors = Zhu T, Liang C, Li D, Tian M, Liu S, Gao G, Guan JS | title = Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1α | journal = Scientific Reports | volume = 6 | pages = 26597 | date = May 2016 | pmid = 27229316 | pmc = 4882582 | doi = 10.1038/srep26597 | bibcode = 2016NatSR...626597Z }} In humans, ASH1L expression peaks prenatally and decreases after birth, with a second peak in expression towards adulthood. In mouse, ASH1L is expressed in the developing central nervous system as early as embryonic day 8.5 {{cite journal | vauthors = Elsen GE, Bedogni F, Hodge RD, Bammler TK, MacDonald JW, Lindtner S, Rubenstein JL, Hevner RF | display-authors = 6 | title = The Epigenetic Factor Landscape of Developing Neocortex Is Regulated by Transcription Factors Pax6→ Tbr2→ Tbr1 | journal = Frontiers in Neuroscience | volume = 12 | pages = 571 | date = 2018 | pmid = 30186101 | pmc = 6113890 | doi = 10.3389/fnins.2018.00571 | doi-access = free }} and is still expressed throughout the adult mouse brain.{{cite journal | vauthors = Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ, Chen L, Chen L, Chen TM, Chin MC, Chong J, Crook BE, Czaplinska A, Dang CN, Datta S, Dee NR, Desaki AL, Desta T, Diep E, Dolbeare TA, Donelan MJ, Dong HW, Dougherty JG, Duncan BJ, Ebbert AJ, Eichele G, Estin LK, Faber C, Facer BA, Fields R, Fischer SR, Fliss TP, Frensley C, Gates SN, Glattfelder KJ, Halverson KR, Hart MR, Hohmann JG, Howell MP, Jeung DP, Johnson RA, Karr PT, Kawal R, Kidney JM, Knapik RH, Kuan CL, Lake JH, Laramee AR, Larsen KD, Lau C, Lemon TA, Liang AJ, Liu Y, Luong LT, Michaels J, Morgan JJ, Morgan RJ, Mortrud MT, Mosqueda NF, Ng LL, Ng R, Orta GJ, Overly CC, Pak TH, Parry SE, Pathak SD, Pearson OC, Puchalski RB, Riley ZL, Rockett HR, Rowland SA, Royall JJ, Ruiz MJ, Sarno NR, Schaffnit K, Shapovalova NV, Sivisay T, Slaughterbeck CR, Smith SC, Smith KA, Smith BI, Sodt AJ, Stewart NN, Stumpf KR, Sunkin SM, Sutram M, Tam A, Teemer CD, Thaller C, Thompson CL, Varnam LR, Visel A, Whitlock RM, Wohnoutka PE, Wolkey CK, Wong VY, Wood M, Yaylaoglu MB, Young RC, Youngstrom BL, Yuan XF, Zhang B, Zwingman TA, Jones AR | display-authors = 6 | title = Genome-wide atlas of gene expression in the adult mouse brain | journal = Nature | volume = 445 | issue = 7124 | pages = 168–176 | date = January 2007 | pmid = 17151600 | doi = 10.1038/nature05453 | bibcode = 2007Natur.445..168L | s2cid = 4421492 }} Overall, the expression of ASH1L in the brain is spatially and temporally broad.

Function

The ASH1L protein is localized to intranuclear speckles and tight junctions, where it was hypothesized to function in adhesion-mediated signaling. 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.{{cite journal | vauthors = Gregory GD, Vakoc CR, Rozovskaia T, Zheng X, Patel S, Nakamura T, Canaani E, Blobel GA | display-authors = 6 | title = Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes | journal = Molecular and Cellular Biology | volume = 27 | issue = 24 | pages = 8466–8479 | date = December 2007 | pmid = 17923682 | pmc = 2169421 | doi = 10.1128/MCB.00993-07 }}

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. 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 myelomonocytic 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.

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. In contrast, two other groups have found that ASH1L's HMTase activity is directed toward H3K36, using nucleosomes as substrate.{{cite journal | vauthors = Tanaka Y, Katagiri Z, Kawahashi K, Kioussis D, Kitajima S | title = Trithorax-group protein ASH1 methylates histone H3 lysine 36 | journal = Gene | volume = 397 | issue = 1–2 | pages = 161–168 | date = August 2007 | pmid = 17544230 | doi = 10.1016/j.gene.2007.04.027 }}

Role in human disease

There are over 100 reported pathogenic, or disease-causing, variants in the ASH1L gene.{{cite journal | vauthors = Faundes V, Newman WG, Bernardini L, Canham N, Clayton-Smith J, Dallapiccola B, Davies SJ, Demos MK, Goldman A, Gill H, Horton R, Kerr B, Kumar D, Lehman A, McKee S, Morton J, Parker MJ, Rankin J, Robertson L, Temple IK, Banka S | display-authors = 6 | title = Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders | journal = American Journal of Human Genetics | volume = 102 | issue = 1 | pages = 175–187 | date = January 2018 | pmid = 29276005 | pmc = 5778085 | doi = 10.1016/j.ajhg.2017.11.013 }}{{cite journal | vauthors = De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD | display-authors = 6 | title = Synaptic, transcriptional and chromatin genes disrupted in autism | journal = Nature | volume = 515 | issue = 7526 | pages = 209–215 | date = November 2014 | pmid = 25363760 | pmc = 4402723 | doi = 10.1038/nature13772 | bibcode = 2014Natur.515..209. }}{{cite journal | vauthors = Grozeva D, Carss K, Spasic-Boskovic O, Tejada MI, Gecz J, Shaw M, Corbett M, Haan E, Thompson E, Friend K, Hussain Z, Hackett A, Field M, Renieri A, Stevenson R, Schwartz C, Floyd JA, Bentham J, Cosgrove C, Keavney B, Bhattacharya S, Hurles M, Raymond FL | display-authors = 6 | title = Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability | journal = Human Mutation | volume = 36 | issue = 12 | pages = 1197–1204 | date = December 2015 | pmid = 26350204 | pmc = 4833192 | doi = 10.1002/humu.22901 }}{{cite journal | vauthors = Okamoto N, Miya F, Tsunoda T, Kato M, Saitoh S, Yamasaki M, Kanemura Y, Kosaki K | display-authors = 6 | title = Novel MCA/ID syndrome with ASH1L mutation | journal = American Journal of Medical Genetics. 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2019 | pmid = 31209962 | pmc = 7428836 | doi = 10.1002/humu.23822 }} About half of the variants arise de novo, and half are inherited. Of the inherited variants, about half are maternally inherited and half are paternally inherited. Disease-causing variants may be missense, nonsense, or frameshift mutations. The missense mutations are distributed throughout the gene body without localizing to a known functional domain of ASH1L.

All affected humans are heterozygous for ASH1L mutations. A single pathogenic copy of ASH1L causes disease, which may be the result of two different genetic mechanisms: haploinsufficiency or dominant negative function. The ClinGen clinical genomics resource states that there is “Sufficient Evidence for Haploinsufficiency” in ASH1L.{{Cite web |title=ASH1L curation results |url=https://search.clinicalgenome.org/kb/genes/HGNC:19088 |access-date=2024-01-22 |website=search.clinicalgenome.org |language=en}}

The most common phenotypes, or symptoms, related to ASH1L mutations are autism spectrum disorder (ASD), epilepsy, intellectual disability, and attention deficit hyperactivity disorder (ADHD). The Simons Foundation Autism Research Initiative (SFARI) gives ASH1L a score of 1.1, indicating that ASH1L is a high confidence autism gene with the best level of evidence linking it to autism.{{Cite web |title=Gene: ASH1L - |url=https://gene.sfari.org/database/human-gene/ASH1L |access-date=2024-01-22 |language=en-US}}

References

External links

{{UCSC gene info|ASH1L}}
Simons Foundation Autism Research Initiative gene page on [https://gene.sfari.org/database/human-gene/ASH1L ASH1L]
Clinical Genome Resource information on [https://search.clinicalgenome.org/kb/genes/HGNC:19088 ASH1L]
[https://www.care4ash1l.com/ CARE4ASH1L] family foundation for families affected by mutations in ASH1L

Category:Enzymes

Category:Genes

Category:Methylation