Alternative titles; symbols
HGNC Approved Gene Symbol: UTY
Cytogenetic location: Yq11.221 Genomic coordinates (GRCh38) : Y:13,233,895-13,480,670 (from NCBI)
Greenfield et al. (1996) described a mouse Y-linked gene, Uty, which is widely expressed and encodes a tetratricopeptide repeat (TPR) protein. TPR motifs are found in a variety of functionally distinct proteins and are believed to mediate protein-protein interaction. The 5.5-kb Uty transcript encodes a 1,186 amino acid protein with 8 TPR motifs in its N terminus. See 300128 for a description of the X-linked homolog of UTY.
Using Northern blot analysis, Lahn and Page (1997) detected at least 2 UTY transcripts in human spleen, thymus, prostate, testis, intestine, colon, and leukocytes, with little to no expression in ovary.
By sequencing PCR products obtained from human hematopoietic cells, leukemic blasts, and primary human fibroblasts, Laaser et al. (2011) isolated 622 UTY clones. Transcript analysis revealed 90 novel splicing events that combine into 284 novel transcripts, in addition to 3 previously reported major variants. Translational analysis revealed a large number of putative UTY proteins ranging in size from 37 to 1,444 amino acids. The longest proteins have an N-terminal signal peptide, followed by a TPR domain split by a transmembrane segment, an unstructured region, an alpha/beta fold, a JmjC-type lysine demethylase domain, and a C-terminal treble-clef zinc finger motif. Alternative splicing preferentially modifies the TPR domain, central region, and C terminus of UTY proteins. The putative signal peptide, JmjC domain, and alpha/beta fold are mainly conserved, with the JmjC domain deleted in rare variants.
By primer walking, Shen et al. (2000) completely sequenced the UTY1 gene and found that it contains 20 exons.
Laaser et al. (2011) determined that the UTY gene has at least 50 exons. The 3-prime UTR has several polyadenylation signals.
Greenfield et al. (1998) reported that the human UTY gene maps to band 5C. This band was known to contain one or more genes functioning in spermatogenesis and a Y-specific growth gene.
Walport et al. (2014) determined the crystal structure of the catalytic C-terminal portion of human KDM6C isoform 3 (residues 878 to 1347) bound to its cosubstrate 2-oxoglutarate to 1.8-angstrom resolution. The structure revealed that the JmjC and zinc-binding domains of KDMC6C are highly similar to the comparable regions of KDM6A (UTX) and KDM6B (611577).
Using yeast 2-hybrid and coimmunoprecipitation analyses, Laaser et al. (2011) found that the central segment (amino acids 278 to 672) encoded by 2 high-frequency cassette exons (exons 12/13b and 15/16) of human UTY variant 26 interacted with AIP (605555) and GNB2L1 (176981).
Walport et al. (2014) found that a recombinant KDM6C C-terminal fragment converted 2-oxoglutarate to succinate and converted trimethyllysine in a histone H3 (see 602810) peptide to dimethyllysine. However, KDM6C activity was significantly lower than that of other KDM6 enzymes. Mutation analysis revealed that replacement of pro1214 in KDM6C with ile1214, which is found in KDM6A and KDM6B, significantly increased KDM6C catalytic activity. Expression of full-length, wildtype KDM6C in HeLa cells did not cause a global reduction of H3 lys27 trimethylation, but it increased expression of an ANF (NPPA; 108780) reporter 5-fold.
Using tissue recombination assays, Dutta et al. (2016) showed that loss of function of Nkx3.1 (602041) in mouse prostate resulted in downregulation of genes essential for prostate differentiation and upregulation of genes not normally expressed in prostate. Gain of function of Nkx3.1 in fully differentiated nonprostate mouse epithelium was sufficient for respecification to prostate in grafts placed under the kidney capsule. In human prostate cells, these activities required interaction of NKX3.1 with G9A methyltransferase (EHMT2; 604599) via the NKX3.1 homeodomain and were mediated by activation of target genes such as UTY. Dutta et al. (2016) proposed that the NKX3.1-EHMT2-UTY transcriptional regulatory network is essential for prostate differentiation and that disruption of such a network predisposes to prostate cancer.
Foresta et al. (2000) reported a complete sequence map of the AZFa region (see 415000), the genomic structure of AZFa genes, and their deletion analysis in 173 infertile men with well-defined spermatogenic alterations. Deletions were found in 9 patients: DBY (400010) alone was deleted in 6, DFFRY (USP9Y; 400005) only in 1, and 1 each with USP9Y-DBY or DBY-UTY missing. No patients solely lacked UTY. Patients lacking DBY exhibited either Sertoli cell-only syndrome or severe hypospermatogenesis. The authors suggested that DBY and USP9Y play key roles in the spermatogenic process.
By use of denaturing HPLC, Shen et al. (2000) screened the UTY1, SMCY (426000), DBY, and DFFRY genes for polymorphic markers in males representative of the 5 continents. Nucleotide diversity was found in the coding regions of 3 of the genes but was not observed in DBY. In agreement with most autosomal genes, diversity estimates for the noncoding regions were about 2- to 3-fold higher than those for coding regions. Pairwise nucleotide mismatch distributions dated the occurrence of population expansion to approximately 28,000 years ago.
Somatic Mutation
Gozdecka et al. (2018) demonstrated that UTX (300128) suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY. In keeping with this, Gozdecka et al. (2018) demonstrated concomitant loss/mutation of KDM6A and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27 trimethylation but significant and bidirectional alterations in H3K27 acetylation and chromatin accessibility; a predominant loss of H3K4 monomethylation modifications; alterations in ETS (see ETS1, 164720) and GATA-factor (see GATA2, 137295) binding; and altered gene expression after UTX loss. By integrating proteomic and genomic analyses, Gozdecka et al. (2018) linked these changes to UTX regulation of ATP-dependent chromatin remodeling, coordination of the COMPASS complex, and enhanced pioneering activity of ETS factors during evolution to acute myeloid leukemia (AML; 601626). Gozdecka et al. (2018) concluded that their findings identified a dual role for UTX in suppressing AML via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programs.
Dutta, A., Le Magnen, C., Mitrofanova, A., Ouyang, X., Califano, A., Abate-Shen, C. Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation. Science 352: 1576-1580, 2016. [PubMed: 27339988] [Full Text: https://doi.org/10.1126/science.aad9512]
Foresta, C., Ferlin, A., Moro, E. Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DBY in male infertility. Hum. Molec. Genet. 9: 1161-1169, 2000. [PubMed: 10767340] [Full Text: https://doi.org/10.1093/hmg/9.8.1161]
Gozdecka, M., Meduri, E., Mazan, M., Tzelepis, K., Dudek, M., Knights, A. J., Pardo, M., Yu, L., Choudhary, J. S., Metzakopian, E., Iyer, V., Yun, H., and 15 others. UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs. Nature Genet. 50: 883-894, 2018. Note: Erratum: Nature Genet. 54: 1062 only, 2022. [PubMed: 29736013] [Full Text: https://doi.org/10.1038/s41588-018-0114-z]
Greenfield, A., Carrel, L., Pennisi, D., Philippe, C., Quaderi, N., Siggers, P., Steiner, K., Tam, P. P. L., Monaco, A. P., Willard, H. F., Koopman, P. The UTX gene escapes X inactivation in mice and humans. Hum. Molec. Genet. 7: 737-742, 1998. [PubMed: 9499428] [Full Text: https://doi.org/10.1093/hmg/7.4.737]
Greenfield, A., Scott, D., Pennisi, D., Ehrmann, I., Ellis, P., Cooper, L., Simpson, E., Koopman, P. An H-YDb epitope is encoded by a novel mouse Y chromosome gene. Nature Genet. 14: 474-478, 1996. [PubMed: 8944031] [Full Text: https://doi.org/10.1038/ng1296-474]
Laaser, I., Theis, F. J., de Angelis, M. H., Kolb, H.-J., Adamski, J. Huge splicing frequency in human Y chromosomal UTY gene. OMICS 15: 141-154, 2011. [PubMed: 21329462] [Full Text: https://doi.org/10.1089/omi.2010.0107]
Lahn, B. T., Page, D. C. Functional coherence of the human Y chromosome. Science 278: 675-680, 1997. [PubMed: 9381176] [Full Text: https://doi.org/10.1126/science.278.5338.675]
Shen, P., Wang, F., Underhill, P. A., Franco, C., Yang, W.-H., Roxas, A., Sung, R., Lin, A. A., Hyman, R. W., Vollrath, D., Davis, R. W., Cavalli-Sforza, L. L., Oefner, P. J. Population genetic implications from sequence variation in four Y chromosome genes. Proc. Nat. Acad. Sci. 97: 7354-7359, 2000. [PubMed: 10861003] [Full Text: https://doi.org/10.1073/pnas.97.13.7354]
Walport, L. J., Hopkinson, R. J., Vollmar, M., Madden, S. K., Gileadi, C., Oppermann, U., Schofield, C. J., Johannson, C. Human UTY(KDM6C) is a male-specific N-methyl lysyl demethylase. J. Biol. Chem. 289: 18302-18313, 2014. [PubMed: 24798337] [Full Text: https://doi.org/10.1074/jbc.M114.555052]