* 604782

ASH2-LIKE; ASH2L


Alternative titles; symbols

ASH2
DROSOPHILA ASH2-LIKE
DROSOPHILA ABSENT, SMALL, OR HOMEOTIC DISCS 2-LIKE
ASH2L1
ASH2L2


HGNC Approved Gene Symbol: ASH2L

Cytogenetic location: 8p11.23     Genomic coordinates (GRCh38): 8:38,105,493-38,140,080 (from NCBI)


TEXT

Description

Methylation of histone H3 (see 602810) lys4 (H3K4) is an important epigenetic modification involved in gene activation. H3K4 di- and trimethylation (H3K4me2 and H3K4me3, respectively) residues mark the transcription start sites of actively transcribed genes, whereas a high level of H3K4 monomethylation (H3K4me1) is associated with enhancer sequences. Members of the SET/MLL protein family, including ASH2L, are responsible for the generation of H3K4me1, H3K4me2, and H3K4me3 marks to induce gene activation and are essential for normal development (summary by Shao et al., 2014).


Cloning and Expression

Drosophila ash2 ('absent, small, or homeotic discs-2') belongs to the trithorax gene family (see 159555). The ash2 product positively regulates expression of homeotic selector genes and is implicated in early development and formation of various disc patterns in the fruit fly. By sequence analysis of a 1.8-Mb fragment of human genomic DNA in 8p11.2, coupled with in silico gene trapping, Ikegawa et al. (1999) identified a gene that is highly homologous to Drosophila ash2; they named the human gene ash2-like (ASH2L). Ikegawa et al. (1999) isolated a full-length ASH2L cDNA encoding a deduced 628-amino acid protein with 93.9% amino acid sequence identity to mouse Ash2l and 45.4% identity to Drosophila ash2. ASH2L contains a predicted PHD zinc finger domain, a putative bipartite nuclear localization signal, potential N-linked glycosylation sites, and potential tyrosine kinase phosphorylation sites. Northern blot analysis detected an approximately 2.6-kb ASH2L transcript in human adult and fetal tissues. ASH2L was ubiquitously expressed, but it was predominantly expressed in adult heart and testis and fetal lung and liver, with barely detectable expression in adult lung, liver, kidney, prostate, and peripheral leukocytes. Ikegawa et al. (1999) suggested that ASH2L functions as a transcriptional regulator.


Gene Function

Wysocka et al. (2003) purified proteins associated with HCF1 (300019) and identified a human trithorax-related SET1 (611052)/ASH2 histone methyltransferase (HMT) complex, the human homolog of S. cerevisiae Set1. Wysocka et al. (2003) showed that, as in yeast, the HCF1-associated human SET1/ASH2 HMT complex possesses histone H3K4 methylation activity, which activates transcription. Furthermore, this activity is blocked by premethylation of K9, a repressor of transcription, indicating that there is crosstalk between K9 methylation and K4 methylation by the SET1/ASH2 complex. The human SET1/ASH2 HMT complex associates with the HCF1 Kelch domain, whereas Sin3 histone deacetylase (HDAC) (see 607776 and 601241), a chromatin-associated complex which represses transcription, associates with the basic region. From subsequent cosedimentation and immunoprecipitation experiments, Wysocka et al. (2003) found that the human SET1/ASH2 complex, in mutually exclusive interactions, can associate with HCF1 bound to Sin3 HDAC or to HCF1 bound to VP16, indicating diverse transcriptional regulatory roles.

Shao et al. (2014) examined the changes of H3K4me and its key regulators in mouse oocytes and preimplantation embryos. They observed increased levels of H3K4me2 and H3K4me3 at the 1- to 2-cell stages, corresponding to the period of embryonic genome activation. The H3K4me2 level dramatically decreased at the 4-cell stage and remained low until the blastocyst stage. In contrast, the H3K4me3 level transiently decreased in 4-cell embryos but steadily increased to peak in blastocysts. Quantitative real-time PCR and immunofluorescence analyses showed that the high level of H3K4me2 during embryonic genome activation coincided with peak expression of its methyltransferase, Ash2l, and a concomitant decrease in its demethylases, Kdm5b (605393) and Kdm1a (609132). H3K4me3 correlated with expression of its methyltransferase, Kmt2b (606834), and demethylase, Kdm5a (180202). Shao et al. (2014) proposed that these enzymes function in embryonic genome activation and first lineage segregation in preimplantation mouse embryos.

Li et al. (2016) demonstrated that a minimized human RBBP5 (600697)-ASH2L heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases (MLL1, 159555; MLL2, 602113; MLL3, 606833; MLL4, 606834; SET1A, 611052; SET1B, 611055). Their structural, biochemical, and computational analyses revealed a 2-step activation mechanism of MLL family proteins. Li et al. (2016) concluded that their findings provided unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggested a universal regulation mechanism for most histone methyltransferases.


Gene Structure

Ikegawa et al. (1999) determined that the ASH2L gene spans more than 34 kb and contains 16 exons. Its transcription is oriented from telomere to centromere.


Mapping

Gross (2014) mapped the ASH2L gene to chromosome 8p11.23 based on an alignment of the ASH2L sequence (GenBank AB022785) with the genomic sequence (GRCh37).


REFERENCES

  1. Gross, M. B. Personal Communication. Baltimore, Md. 3/14/2014.

  2. Ikegawa, S., Isomura, M., Koshizuka, Y., Nakamura, Y. Cloning and characterization of ASH2L and Ash2l, human and mouse homologs of the Drosophila ash2 gene. Cytogenet. Cell Genet. 84: 167-172, 1999. [PubMed: 10393421, related citations] [Full Text]

  3. Li, Y., Han, J., Zhang, Y., Cao, F., Liu, Z., Li, S., Wu, J., Hu, C., Wang, Y., Shuai, J., Chen, J., Cao, L., Li, D., Shi, P., Tian, C., Zhang, J., Dou, Y., Li, G., Chen, Y., Lei, M. Structural basis for activity regulation of MLL family methyltransferases. Nature 530: 447-452, 2016. [PubMed: 26886794, images, related citations] [Full Text]

  4. Shao, G.-B., Chen, J.-C., Zhang, L.-P., Huang, P., Lu, H.-Y., Jin, J., Gong, A.-H., Sang, J.-R. Dynamic patterns of histone H3 lysine 4 methyltransferases and demethylases during mouse preimplantation development. In Vitro Cell. Dev. Biol. Anim. 50: 603-613, 2014. [PubMed: 24619213, related citations] [Full Text]

  5. Wysocka, J., Myers, M. P., Laherty, C. D., Eisenman, R. N., Herr, W. Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev. 17: 896-911, 2003. [PubMed: 12670868, images, related citations] [Full Text]


Ada Hamosh - updated : 12/19/2016
Matthew B. Gross - updated : 3/14/2014
Jennifer L. Goldstein - updated : 5/23/2007
Creation Date:
Patti M. Sherman : 4/3/2000
alopez : 12/19/2016
carol : 08/23/2016
mcolton : 01/30/2015
mgross : 3/14/2014
mgross : 3/14/2014
carol : 5/23/2007
mcapotos : 4/18/2000
psherman : 4/5/2000

* 604782

ASH2-LIKE; ASH2L


Alternative titles; symbols

ASH2
DROSOPHILA ASH2-LIKE
DROSOPHILA ABSENT, SMALL, OR HOMEOTIC DISCS 2-LIKE
ASH2L1
ASH2L2


HGNC Approved Gene Symbol: ASH2L

Cytogenetic location: 8p11.23     Genomic coordinates (GRCh38): 8:38,105,493-38,140,080 (from NCBI)


TEXT

Description

Methylation of histone H3 (see 602810) lys4 (H3K4) is an important epigenetic modification involved in gene activation. H3K4 di- and trimethylation (H3K4me2 and H3K4me3, respectively) residues mark the transcription start sites of actively transcribed genes, whereas a high level of H3K4 monomethylation (H3K4me1) is associated with enhancer sequences. Members of the SET/MLL protein family, including ASH2L, are responsible for the generation of H3K4me1, H3K4me2, and H3K4me3 marks to induce gene activation and are essential for normal development (summary by Shao et al., 2014).


Cloning and Expression

Drosophila ash2 ('absent, small, or homeotic discs-2') belongs to the trithorax gene family (see 159555). The ash2 product positively regulates expression of homeotic selector genes and is implicated in early development and formation of various disc patterns in the fruit fly. By sequence analysis of a 1.8-Mb fragment of human genomic DNA in 8p11.2, coupled with in silico gene trapping, Ikegawa et al. (1999) identified a gene that is highly homologous to Drosophila ash2; they named the human gene ash2-like (ASH2L). Ikegawa et al. (1999) isolated a full-length ASH2L cDNA encoding a deduced 628-amino acid protein with 93.9% amino acid sequence identity to mouse Ash2l and 45.4% identity to Drosophila ash2. ASH2L contains a predicted PHD zinc finger domain, a putative bipartite nuclear localization signal, potential N-linked glycosylation sites, and potential tyrosine kinase phosphorylation sites. Northern blot analysis detected an approximately 2.6-kb ASH2L transcript in human adult and fetal tissues. ASH2L was ubiquitously expressed, but it was predominantly expressed in adult heart and testis and fetal lung and liver, with barely detectable expression in adult lung, liver, kidney, prostate, and peripheral leukocytes. Ikegawa et al. (1999) suggested that ASH2L functions as a transcriptional regulator.


Gene Function

Wysocka et al. (2003) purified proteins associated with HCF1 (300019) and identified a human trithorax-related SET1 (611052)/ASH2 histone methyltransferase (HMT) complex, the human homolog of S. cerevisiae Set1. Wysocka et al. (2003) showed that, as in yeast, the HCF1-associated human SET1/ASH2 HMT complex possesses histone H3K4 methylation activity, which activates transcription. Furthermore, this activity is blocked by premethylation of K9, a repressor of transcription, indicating that there is crosstalk between K9 methylation and K4 methylation by the SET1/ASH2 complex. The human SET1/ASH2 HMT complex associates with the HCF1 Kelch domain, whereas Sin3 histone deacetylase (HDAC) (see 607776 and 601241), a chromatin-associated complex which represses transcription, associates with the basic region. From subsequent cosedimentation and immunoprecipitation experiments, Wysocka et al. (2003) found that the human SET1/ASH2 complex, in mutually exclusive interactions, can associate with HCF1 bound to Sin3 HDAC or to HCF1 bound to VP16, indicating diverse transcriptional regulatory roles.

Shao et al. (2014) examined the changes of H3K4me and its key regulators in mouse oocytes and preimplantation embryos. They observed increased levels of H3K4me2 and H3K4me3 at the 1- to 2-cell stages, corresponding to the period of embryonic genome activation. The H3K4me2 level dramatically decreased at the 4-cell stage and remained low until the blastocyst stage. In contrast, the H3K4me3 level transiently decreased in 4-cell embryos but steadily increased to peak in blastocysts. Quantitative real-time PCR and immunofluorescence analyses showed that the high level of H3K4me2 during embryonic genome activation coincided with peak expression of its methyltransferase, Ash2l, and a concomitant decrease in its demethylases, Kdm5b (605393) and Kdm1a (609132). H3K4me3 correlated with expression of its methyltransferase, Kmt2b (606834), and demethylase, Kdm5a (180202). Shao et al. (2014) proposed that these enzymes function in embryonic genome activation and first lineage segregation in preimplantation mouse embryos.

Li et al. (2016) demonstrated that a minimized human RBBP5 (600697)-ASH2L heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases (MLL1, 159555; MLL2, 602113; MLL3, 606833; MLL4, 606834; SET1A, 611052; SET1B, 611055). Their structural, biochemical, and computational analyses revealed a 2-step activation mechanism of MLL family proteins. Li et al. (2016) concluded that their findings provided unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggested a universal regulation mechanism for most histone methyltransferases.


Gene Structure

Ikegawa et al. (1999) determined that the ASH2L gene spans more than 34 kb and contains 16 exons. Its transcription is oriented from telomere to centromere.


Mapping

Gross (2014) mapped the ASH2L gene to chromosome 8p11.23 based on an alignment of the ASH2L sequence (GenBank AB022785) with the genomic sequence (GRCh37).


REFERENCES

  1. Gross, M. B. Personal Communication. Baltimore, Md. 3/14/2014.

  2. Ikegawa, S., Isomura, M., Koshizuka, Y., Nakamura, Y. Cloning and characterization of ASH2L and Ash2l, human and mouse homologs of the Drosophila ash2 gene. Cytogenet. Cell Genet. 84: 167-172, 1999. [PubMed: 10393421] [Full Text: https://doi.org/10.1159/000015248]

  3. Li, Y., Han, J., Zhang, Y., Cao, F., Liu, Z., Li, S., Wu, J., Hu, C., Wang, Y., Shuai, J., Chen, J., Cao, L., Li, D., Shi, P., Tian, C., Zhang, J., Dou, Y., Li, G., Chen, Y., Lei, M. Structural basis for activity regulation of MLL family methyltransferases. Nature 530: 447-452, 2016. [PubMed: 26886794] [Full Text: https://doi.org/10.1038/nature16952]

  4. Shao, G.-B., Chen, J.-C., Zhang, L.-P., Huang, P., Lu, H.-Y., Jin, J., Gong, A.-H., Sang, J.-R. Dynamic patterns of histone H3 lysine 4 methyltransferases and demethylases during mouse preimplantation development. In Vitro Cell. Dev. Biol. Anim. 50: 603-613, 2014. [PubMed: 24619213] [Full Text: https://doi.org/10.1007/s11626-014-9741-6]

  5. Wysocka, J., Myers, M. P., Laherty, C. D., Eisenman, R. N., Herr, W. Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev. 17: 896-911, 2003. [PubMed: 12670868] [Full Text: https://doi.org/10.1101/gad.252103]


Contributors:
Ada Hamosh - updated : 12/19/2016
Matthew B. Gross - updated : 3/14/2014
Jennifer L. Goldstein - updated : 5/23/2007

Creation Date:
Patti M. Sherman : 4/3/2000

Edit History:
alopez : 12/19/2016
carol : 08/23/2016
mcolton : 01/30/2015
mgross : 3/14/2014
mgross : 3/14/2014
carol : 5/23/2007
mcapotos : 4/18/2000
psherman : 4/5/2000