Biology:ASH1L

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1] Drosophila Ash1 interacts with trithorax to regulate ultrabithorax expression.[2]

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.[3]

Structure

Human ASH1L protein is 2969 amino acids long with a molecular weight of 333 kDa.[4] 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.[3] 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.[5]

Function

The ASH1L protein is localized to intranuclear speckles and tight junctions, where it was hypothesized to function in adhesion-mediated signaling.[3] 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.[6]

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.[1]

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.[6] In contrast, two other groups have found that ASH1L’s HMTase activity is directed toward H3K36, using nucleosomes as substrate.[5][7]

Role in disease

There are over 100 reported pathogenic, or disease-causing, variants in the ASH1L gene.[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] 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.[32]

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.[33]

References

  1. ↑ 1.0 1.1 "Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression". PLOS ONE 6 (11): e28171. 2011. doi:10.1371/journal.pone.0028171. PMID 22140534. Bibcode: 2011PLoSO...628171T. 
  2. ↑ "Trithorax and ASH1 interact directly and associate with the trithorax group-responsive bxd region of the Ultrabithorax promoter". Molecular and Cellular Biology 19 (9): 6441–6447. September 1999. doi:10.1128/MCB.19.9.6441. PMID 10454589. 
  3. ↑ 3.0 3.1 3.2 "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". Proceedings of the National Academy of Sciences of the United States of America 97 (13): 7284–7289. June 2000. doi:10.1073/pnas.97.13.7284. PMID 10860993. Bibcode: 2000PNAS...97.7284N. 
  4. ↑ "ASH1L_HUMAN". UniProt. https://www.uniprot.org/uniprot/Q9NR48. 
  5. ↑ 5.0 5.1 "Crystal structure of the human histone methyltransferase ASH1L catalytic domain and its implications for the regulatory mechanism". The Journal of Biological Chemistry 286 (10): 8369–8374. March 2011. doi:10.1074/jbc.M110.203380. PMID 21239497. 
  6. ↑ 6.0 6.1 "Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes". Molecular and Cellular Biology 27 (24): 8466–8479. December 2007. doi:10.1128/MCB.00993-07. PMID 17923682. 
  7. ↑ "Trithorax-group protein ASH1 methylates histone H3 lysine 36". Gene 397 (1–2): 161–168. August 2007. doi:10.1016/j.gene.2007.04.027. PMID 17544230. 
  8. ↑ "Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders". American Journal of Human Genetics 102 (1): 175–187. January 2018. doi:10.1016/j.ajhg.2017.11.013. PMID 29276005. 
  9. ↑ "Synaptic, transcriptional and chromatin genes disrupted in autism". Nature 515 (7526): 209–215. November 2014. doi:10.1038/nature13772. PMID 25363760. Bibcode: 2014Natur.515..209.. 
  10. ↑ "Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability". Human Mutation 36 (12): 1197–1204. December 2015. doi:10.1002/humu.22901. PMID 26350204. 
  11. ↑ "Novel MCA/ID syndrome with ASH1L mutation". American Journal of Medical Genetics. Part A 173 (6): 1644–1648. June 2017. doi:10.1002/ajmg.a.38193. PMID 28394464. 
  12. ↑ "De novo loss-of-function variants of ASH1L are associated with an emergent neurodevelopmental disorder". European Journal of Medical Genetics 62 (1): 55–60. January 2019. doi:10.1016/j.ejmg.2018.05.003. PMID 29753921. 
  13. ↑ "ASH1L mutation caused seizures and intellectual disability in twin sisters". Journal of Clinical Neuroscience 91: 69–74. September 2021. doi:10.1016/j.jocn.2021.06.038. PMID 34373061. 
  14. ↑ "Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder". JAMA 314 (9): 895–903. September 2015. doi:10.1001/jama.2015.10078. PMID 26325558. 
  15. ↑ "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies". Science 350 (6265): 1262–1266. December 2015. doi:10.1126/science.aac9396. PMID 26785492. Bibcode: 2015Sci...350.1262H. 
  16. ↑ "Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures". Epilepsia 61 (5): 995–1007. May 2020. doi:10.1111/epi.16508. PMID 32469098. 
  17. ↑ "Diagnostic exome sequencing in persons with severe intellectual disability". The New England Journal of Medicine 367 (20): 1921–1929. November 2012. doi:10.1056/NEJMoa1206524. PMID 23033978. 
  18. ↑ "De novo genic mutations among a Chinese autism spectrum disorder cohort". Nature Communications 7: 13316. November 2016. doi:10.1038/ncomms13316. PMID 27824329. Bibcode: 2016NatCo...713316W. 
  19. ↑ "Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders". Nature Communications 11 (1): 4932. October 2020. doi:10.1038/s41467-020-18723-y. PMID 33004838. Bibcode: 2020NatCo..11.4932W. 
  20. ↑ "The contribution of de novo coding mutations to autism spectrum disorder". Nature 515 (7526): 216–221. November 2014. doi:10.1038/nature13908. PMID 25363768. Bibcode: 2014Natur.515..216I. 
  21. ↑ "Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases". Nature Genetics 49 (4): 515–526. April 2017. doi:10.1038/ng.3792. PMID 28191889. 
  22. ↑ "Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks". Cell 178 (4): 850–866.e26. August 2019. doi:10.1016/j.cell.2019.07.015. PMID 31398340. 
  23. ↑ "Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism". Cell 155 (5): 997–1007. November 2013. doi:10.1016/j.cell.2013.10.020. PMID 24267886. 
  24. ↑ "Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model". Molecular Autism 9: 64. 2018. doi:10.1186/s13229-018-0247-z. PMID 30564305. 
  25. ↑ "Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes". Nature Genetics 54 (9): 1305–1319. September 2022. doi:10.1038/s41588-022-01148-2. PMID 35982159. 
  26. ↑ "Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder". Nature Neuroscience 20 (4): 602–611. April 2017. doi:10.1038/nn.4524. PMID 28263302. 
  27. ↑ "Excess of rare, inherited truncating mutations in autism". Nature Genetics 47 (6): 582–588. June 2015. doi:10.1038/ng.3303. PMID 25961944. 
  28. ↑ "High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population". American Journal of Human Genetics 108 (10): 1981–2005. October 2021. doi:10.1016/j.ajhg.2021.08.009. PMID 34582790. 
  29. ↑ "Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes". Nature Genetics 54 (9): 1305–1319. September 2022. doi:10.1038/s41588-022-01148-2. PMID 35982159. 
  30. ↑ "Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings". Genes 12 (7): 1053. July 2021. doi:10.3390/genes12071053. PMID 34356069. 
  31. ↑ "Characterization of intellectual disability and autism comorbidity through gene panel sequencing". Human Mutation 40 (9): 1346–1363. September 2019. doi:10.1002/humu.23822. PMID 31209962. 
  32. ↑ "ASH1L curation results" (in en). https://search.clinicalgenome.org/kb/genes/HGNC:19088. 
  33. ↑ "Gene: ASH1L -" (in en-US). https://gene.sfari.org/database/human-gene/ASH1L. 

External links

  • Human ASH1L genome location and ASH1L gene details page in the UCSC Genome Browser.
  • Simons Foundation Autism Research Initiative gene page on ASH1L
  • Clinical Genome Resource information on ASH1L
  • CARE4ASH1L family foundation for families affected by mutations in ASH1L

Further reading



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