Alternative titles; symbols
HGNC Approved Gene Symbol: L3MBTL1
Cytogenetic location: 20q13.12 Genomic coordinates (GRCh38) : 20:43,507,697-43,550,954 (from NCBI)
L3MBTL encodes a member of the polycomb family of proteins (see CBX4; 603079), which, together with trithorax group proteins (see MLL; 159555), coordinate patterns of gene activity (Li et al., 2004).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Ishikawa et al. (1998) cloned L3MBTL, which they designated KIAA0681. The deduced protein shares 35.9% identity over 259 amino acids with the Drosophila transcriptional repressor Scm (see SCML1; 300227). RT-PCR detected L3MBTL expression in all tissues examined.
By searching an EST database for sequences similar to the Drosophila lethal(3)malignant brain tumor gene (L3mt), followed by PCR of a fetal brain cDNA library, Koga et al. (1999) cloned 2 splice variants of L3MBTL. One variant, L3MBT-I, encodes a deduced 772-amino acid protein. The other, L3MBT-II, has a 118-bp insertion and encodes a deduced 738-amino acid protein that is truncated at the C terminus. Both isoforms contain 3 central mbt repeats, followed by a C2HC zinc finger and a 60-amino acid SPM domain (see SCML2; 300208). Both also have 3 putative nuclear localization signals. Northern blot analysis detected wide expression of a 4.7-kb L3MBTL transcript in normal tissues and in some cancer cell lines. RT-PCR analysis detected variable expression of both variants in all samples of peripheral blood lymphocytes from 20 normal volunteers. Western blot analysis detected variable levels of L3MBTL in several cancer cell lines; the apparent molecular mass was about 100 kD. Immunocytochemical analysis of an osteosarcoma cell line showed L3MBTL weakly expressed in the nucleoplasm during interphase. Mitotic cells between prophase and telophase showed intense and punctate L3MBTL staining that was associated with condensed chromosomes and was excluded from nucleoli. L3MBTL did not colocalize with BMI1 (164831) in interphase nuclei. Koga et al. (1999) concluded that, since Western blot analysis indicated that the L3MBTL protein level did not change during the cell cycle, the changes in L3MBTL nuclear distribution reflected changes in chromatin organization.
By Northern blot analysis of mouse tissues, Qin et al. (2010) found that L3mbtl1 was highly expressed in brain, followed by testis, eye, and embryonic stem cells. RT-PCR detected widespread L3mbtl1 expression, including in the gastrointestinal system, hematolymphoid system, kidney, ovary, and bladder.
Li et al. (2004) determined that the L3MBTL gene contains 24 exons and spans 45 kb. It has 2 putative promoters, one upstream of exon 1 and the other upstream of exon 5a. The L3MBTL gene also has 4 CpG islands: CpG islands 1 and 2 span promoter 1, and CpG islands 3 and 4 are in the vicinity of exons 4 and 5.
By radiation hybrid analysis, Ishikawa et al. (1998) mapped the L3MBTL gene to chromosome 20. Koga et al. (1999) mapped the L3MBTL gene to chromosome 20q12 by radiation hybrid analysis and FISH.
Stumpf (2021) mapped the L3MBTL1 gene to chromosome 20q13.12 based on an alignment of the L3MBTL1 sequence (GenBank BC039820) with the genomic sequence (GRCh38).
Koga et al. (1999) found that overexpression of L3MBTL in a malignant glioma cell line led to failure of proper chromosome segregation and cytokinesis, resulting in the formation of multinucleated cells.
Li et al. (2007) stated that the L3MBTL protein contains 3 MBT repeats, each with its own pocket. Using quantitative binding and crystallographic analysis of the MBT repeats of L3MBTL bound to synthetic peptides, they showed that pocket-1 bound the proline ring of a pro-ser-ser/thr sequence and that pocket-2 bound histone tail peptides containing monomethyllysine and dimethyllysine, but not trimethyllysine.
Using sucrose gradient sedimentation to reconstitute L3MBTL1-histone complexes, followed by electron microscopy, Western blot analysis, and chromatin immunoprecipitation analysis, Trojer et al. (2007) showed that L3MBTL1 compacted nucleosomal arrays in a manner that required specific posttranslational modification within core and/or linker histones. The second MBT domain of L3MBTL1 exclusively recognized the mono- and dimethyl versions of both lys20 of H4 (see 602822) and lys26 of H1B (HIST1H1B; 142711), respectively. Trojer et al. (2007) concluded that L3MBTL1, together with HP1-gamma (CBX3; 604477), is involved in the readout of multiple lysine methylation marks within histones H1B, H3 (see 142780), and H4, possibly leading to a combinatorial pattern of histone modifications resulting in chromatin condensation of E2F (189971)- and Rb1 (614041)-regulated genes.
Mutations in the Drosophila gene lethal-3-malignant brain tumor (l(3)mbt) cause malignant growth in the larval brain. Janic et al. (2010) showed that l(3)mbt tumors exhibited a soma-to-germline transformation through the ectopic expression of genes normally required for germline stemness, fitness, or longevity. Orthologs of some of these genes were also expressed in human somatic tumors. In addition, inactivation of any of the germline genes nanos (see 608226), vasa (605281), piwi (see 605571), or aubergine suppressed l(3)mbt malignant growth. Janic et al. (2010) demonstrated that germline traits are necessary for tumor growth in this Drosophila model and suggested that inactivation of germline genes might have tumor-suppressing effects in other species.
Li et al. (2004) demonstrated monoallelic methylation of CpG islands 3 and 4 in the L3MBTL gene in hematopoietic cells from normal individuals, and the methylation correlated with transcriptional silencing of the L3MBTL gene. Transcription of the L3MBTL gene occurred from the paternally derived allele in 5 individuals from 2 families. Expression of the paternally derived allele was observed in multiple hematopoietic cell types, as well as in bone marrow-derived mesenchymal cells. Chromosome 20q deletions associated with myeloid malignancies resulted in loss of either the unmethylated or methylated allele.
Qin et al. (2010) found that L3mbtl1 -/- mice developed and reproduced normally and had a normal life span. Brain development and function appeared normal, and no abnormalities were detected in other tissues. No abnormalities were detected in cell cycle progression, chromatin density, histone methylation, cell cycle arrest in response to irradiation, and survival after sublethal irradiation. Qin et al. (2010) concluded that L3mbtl1 is dispensable for development and tumor suppression in mice.
Ishikawa, K., Nagase, T., Suyama, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 169-176, 1998. [PubMed: 9734811] [Full Text: https://doi.org/10.1093/dnares/5.3.169]
Janic, A., Mendizabal, L., Llamazares, S., Rossell, D., Gonzalez, C. Ectopic expression of germline genes drives malignant brain tumor growth in Drosophila. Science 330: 1824-1827, 2010. [PubMed: 21205669] [Full Text: https://doi.org/10.1126/science.1195481]
Koga, H., Matsui, S., Hirota, T., Takebayashi, S., Okumura, K., Saya, H. A human homolog of Drosophila lethal(3)malignant brain tumor (l(3)mbt) protein associates with condensed mitotic chromosomes. Oncogene 18: 3799-3809, 1999. [PubMed: 10445843] [Full Text: https://doi.org/10.1038/sj.onc.1202732]
Li, H., Fischle, W., Wang, W., Duncan, E. M., Liang, L., Murakami-Ishibe, S., Allis, C. D., Patel, D. J. Structural basis for lower lysine methylation state-specific readout by MBT repeats of L3MBTL1 and an engineered PHD finger. Molec. Cell 28: 677-691, 2007. [PubMed: 18042461] [Full Text: https://doi.org/10.1016/j.molcel.2007.10.023]
Li, J., Bench, A. J., Vassiliou, G. S., Fourouclas, N., Ferguson-Smith, A. C., Green, A. R. Imprinting of the human L3MBTL gene, a polycomb family member located in a region of chromosome 20 deleted in human myeloid malignancies. Proc. Nat. Acad. Sci. 101: 7341-7346, 2004. Note: Erratum: Proc. Nat. Acad. Sci. 118: e2101413118, 2021. [PubMed: 15123827] [Full Text: https://doi.org/10.1073/pnas.0308195101]
Qin, J., Van Buren, D., Huang, H.-S., Zhong, L., Mostoslavsky, R., Akbarian, S., Hock, H. Chromatin protein L3MBTL1 is dispensable for development and tumor suppression in mice. J. Biol. Chem. 285: 27767-27775, 2010. [PubMed: 20592034] [Full Text: https://doi.org/10.1074/jbc.M110.115410]
Stumpf, A. M. Personal Communication. Baltimore, Md. 04/14/2021.
Trojer, P., Li, G., Sims, R. J., III, Vaquero, A., Kalakonda, N., Boccuni, P., Lee, D., Erdjument-Bromage, H., Tempst, P., Nimer, S. D., Wang, Y.-H., Reinberg, D. L3MBTL1, a histone-methylation-dependent chromatin lock. Cell 129: 915-928, 2007. [PubMed: 17540172] [Full Text: https://doi.org/10.1016/j.cell.2007.03.048]