HGNC Approved Gene Symbol: ELL2
Cytogenetic location: 5q15 Genomic coordinates (GRCh38): 5:95,885,098-95,961,851 (from NCBI)
ELL2 encodes a key component of the super-elongation complex that drives secretory-specific immunoglobulin (Ig) mRNA production and transcriptional regulation in plasma cells (Park et al., 2014; Li et al., 2017).
The elongation stage of eukaryotic mRNA synthesis is a major site for the regulation of gene expression. Moreover, there is evidence that misregulation of transcription elongation may be a key element in a variety of human diseases. The ELL gene (600284) on 19p13.1 was originally isolated as a gene that undergoes frequent translocations with the MLL gene (159555) on 11q23 in acute myeloid leukemia. ELL encodes an elongation factor that can increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. As part of an effort to understand how elongation by RNA polymerase II is controlled under normal cell conditions and in disease, Shilatifard et al. (1997) initiated a search for ELL-related proteins. They described the identification and characterization of ELL2, a novel ELL-related RNA polymerase II elongation factor. ELL2 encodes a predicted 640-amino acid protein that is 49% identical ELL. Mechanistic studies indicated that ELL2 and ELL possess similar transcriptional activities. Structure-function studies localized the ELL2 elongation activation domain to an ELL2 N-terminal region that is highly homologous to ELL. Northern blot analysis revealed expression of 6- and 4.1-kb ELL2 transcripts. ELL2 and ELL were transcribed in many of the same tissues, but the ratio of their transcripts exhibited tissue-to-tissue variation, raising the possibility that ELL2 and ELL may not perform completely general functions, but instead, may perform gene- or tissue-specific functions.
Li et al. (2017) stated that the ELL2 gene maps to chromosome 5q15.
Li et al. (2017) noted that genomewide association studies have suggested that variation at chromosome 5q15 influences risk of multiple myeloma (MM; 254500). They identified a G-C SNP, rs6877329, within a predicted enhancer element that physically interacted with the transcription start site of ELL2. The C risk allele of rs6877329 was associated with reduced enhancer activity and lower ELL2 expression. Li et al. (2017) proposed that reduced ELL2 expression may contribute to arrest of plasma-cell development and facilitate MM clonal expansion.
Park et al. (2014) found that mice with B cell-specific deletion of Ell2 exhibited curtailed humoral responses and diminished recall immune responses. The mutant mice had increased immature and recirculating B cells in bone marrow, whereas splenic plasma cells were reduced. IgG1-producing B cells were reduced in bone marrow of mutant mice. Ex vivo-stimulated splenic B cells from mutant mice had a paucity of secreted IgH and an abnormal appearing endoplasmic reticulum. These and additional findings led Park et al. (2014) to propose that ELL2 is important antibody secretion, XBP1 (194355) expression, and the unfolded protein response.
Li, N., Johnson, D. C., Weinhold, N., Kimber, S., Dobbins, S. E., Mitchell, J. S., Kinnersley, B., Sud, A., Law, P. J., Orlando, G., Scales, M., Wardell, C. P., and 12 others. Genetic predisposition to multiple myeloma at 5q15 is mediated by an ELL2 enhancer polymorphism. Cell Rep. 20: 2556-2564, 2017. [PubMed: 28903037] [Full Text: https://doi.org/10.1016/j.celrep.2017.08.062]
Park, K. S., Bayles, I., Szlachta-McGinn, A., Paul, J., Boiko, J., Santos, P., Liu, J., Wang, Z., Borghesi, L., Milcarek, C. Transcription elongation factor ELL2 drives Ig secretory-specific mRNA production and the unfolded protein response. J. Immun. 193: 4663-4674, 2014. [PubMed: 25238757] [Full Text: https://doi.org/10.4049/jimmunol.1401608]
Shilatifard, A., Duan, D. R., Haque, D., Florence, C., Schubach, W. H., Conaway, J. W., Conaway, R. C. ELL2, a new member of an ELL family of RNA polymerase II elongation factors. Proc. Nat. Acad. Sci. 94: 3639-3643, 1997. [PubMed: 9108030] [Full Text: https://doi.org/10.1073/pnas.94.8.3639]