# UTY Gene: Structure, Function, and Clinical Significance ## Key Takeaways - The UTY gene, located on the Y chromosome, encodes a histone H3 lysine 27 (H3K27) demethylase, though its catalytic activity is significantly weaker than its X-linked paralog, KDM6A, often functioning primarily as a scaffold protein. - UTY plays a critical role in chromatin remodeling by interacting with the SWI/SNF complex and is involved in regulating gene expression during development, cell cycle progression, and DNA damage response pathways. - Somatic mutations in UTY are prevalent in male-specific cancers such as bladder and prostate cancer, where loss of function is associated with aggressive tumor subtypes and therapeutic resistance. - Germline mutations in UTY are rare but can contribute to male-specific phenotypes resembling Kabuki syndrome, impacting chromatin remodeling and developmental processes. - UTY serves as a source of H-Y minor histocompatibility antigens, influencing graft-versus-leukemia effects and graft-versus-host disease in sex-mismatched hematopoietic stem cell transplantation, and is a target for immunotherapeutic strategies. - Viral pathogens like HPV and KSHV can hijack UTY's epigenetic regulatory functions to promote their replication and maintain latency, highlighting its role in host-pathogen interactions. --- ## Executive Summary & Key Metadata The UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Gene, Y-linked) gene encodes a histone demethylase that specifically removes methyl groups from lysine 27 of histone H3 (H3K27). As a Y-chromosome-encoded paralog of the X-linked KDM6A (UTX) gene, UTY is a critical epigenetic regulator with sex-specific implications in development, immunity, and oncogenesis. Unlike KDM6A, UTY exhibits a catalytically inactivated JmjC domain in most isoforms, yet retains significant scaffolding and regulatory functions. This manual provides a comprehensive, biophysically grounded analysis of UTY's genomic architecture, protein structure, signaling networks, pathogenic mutations, and therapeutic relevance. | **Attribute** | **Detail** | | :--- | :--- | | **HGNC Symbol** | UTY | | **UniProt Accession** | O14607 | | **Representative PDB ID** | True (Homology models based on KDM6A; see Section 2) | | **Chromosomal Locus** | Yq11.221 (GRCh38: chrY:13,455,000–13,680,000) | | **Primary Molecular Function** | Histone H3K27 demethylase (catalytically weak/absent in most isoforms); transcriptional co-regulator; chromatin remodeling | | **Disease & Pathology Associations** | Sex-biased cancers (prostate, bladder, glioblastoma), Kabuki syndrome (via KDM6A interplay), graft-versus-host disease (H-Y antigen), male infertility | --- ## 1. Genomic Locus, Chromosomal Organization & Isoforms ### 1.1 Chromosomal Context and Synteny The UTY gene is located on the long arm of the Y chromosome at band q11.221, a region known as the male-specific region of the Y chromosome (MSY). This locus is characterized by a high density of palindromic sequences and ampliconic repeats, which predispose the region to structural rearrangements and copy number variations. The gene spans approximately 225 kilobases (kb) of genomic DNA on the minus strand (NCBI Reference Sequence: NC_000024.10). Its X-chromosomal counterpart, KDM6A (UTX), resides at Xp11.3. Both genes share a common evolutionary ancestor, with UTY having diverged significantly in its enzymatic capacity while retaining high sequence homology in its protein-binding domains [1]. The UTY locus is embedded within a gene-dense region, flanked by the *TBL1Y* (transducin beta-like 1, Y-linked) gene upstream and the *NLGN4Y* (neuroligin 4, Y-linked) gene downstream. This syntenic block is conserved across eutherian mammals, although the Y-linked copy has undergone lineage-specific degeneration in some species. The promoter region of UTY lacks a canonical TATA box but contains a high-density CpG island, characteristic of housekeeping genes that require constitutive expression across all tissues. This CpG island spans approximately 1.5 kb upstream of the transcription start site (TSS) and is a target for DNA methylation-mediated silencing in specific cellular contexts [2]. ### 1.2 Promoter Architecture and Regulatory Elements The UTY promoter is regulated by a complex interplay of transcription factors. Chromatin immunoprecipitation sequencing (ChIP-seq) data from the ENCODE project reveal constitutive binding of RNA Polymerase II (Pol II) and the transcription factor SP1 at the core promoter. Additionally, several enhancer elements have been identified within the first intron, which is unusually large (~80 kb). These intronic enhancers are marked by H3K4me1 and H3K27ac histone modifications in embryonic stem cells and are bound by pluripotency factors such as OCT4 and NANOG. This suggests that UTY expression is not merely ubiquitous but is dynamically regulated during early development and cellular differentiation [3]. A critical regulatory feature is the presence of a long non-coding RNA (lncRNA) gene, *UTY-AS1*, transcribed antisense to UTY. This lncRNA has been shown to recruit the Polycomb Repressive Complex 2 (PRC2) to the UTY promoter in a cell-type-specific manner, leading to H3K27me3 deposition and transcriptional repression. This antisense regulation provides a mechanism for the observed downregulation of UTY in certain cancers, despite its general housekeeping role [4]. ### 1.3 Alternative Splicing and Isoform Diversity The UTY gene undergoes extensive alternative splicing, generating multiple transcript variants that encode distinct protein isoforms. The primary transcript consists of 29 exons, with the translation initiation codon located in exon 2. The major protein isoform (Isoform 1, UniProt O14607-1) is 1347 amino acids long. However, at least five other protein-coding isoforms have been cataloged in Ensembl, resulting from alternative promoter usage and exon skipping events. The most functionally significant splice variant involves exon 11, which encodes a portion of the JmjC domain. Skipping of exon 11 produces a truncated protein lacking the catalytic core, which acts as a dominant-negative regulator of the full-length protein. This isoform is preferentially expressed in testicular tissue, suggesting a role in spermatogenesis. Additionally, a testis-specific promoter located within intron 5 drives the expression of a short isoform (Isoform 5) that lacks the N-terminal TPR domains. This isoform retains the C-terminal JmjC domain but lacks nuclear localization signals, resulting in cytoplasmic retention and potential non-genomic functions [5]. --- ## 2. 3D Protein Domain Architecture & Structural Biology ### 2.1 Domain Organization The UTY protein is a large, multi-domain protein that can be structurally divided into two major functional regions: an N-terminal regulatory region and a C-terminal catalytic region. The domain architecture is highly similar to KDM6A, with critical differences in the catalytic pocket. - **N-Terminal Tetratricopeptide Repeat (TPR) Domain (Residues 1–350):** This region contains multiple TPR motifs, each consisting of a 34-amino acid degenerate repeat that folds into a helix-turn-helix structure. Tandem arrays of TPR motifs form a superhelical groove that mediates protein-protein interactions. In UTY, this domain is responsible for binding to the SWI/SNF chromatin remodeling complex, specifically the BRG1 (SMARCA4) and BAF155 (SMARCC1) subunits. This interaction is essential for UTY's ability to modulate chromatin accessibility independent of its demethylase activity [6]. - **Linker Region (Residues 351–900):** This intrinsically disordered region is poorly conserved between UTY and KDM6A. It contains multiple phosphorylation sites for kinases such as CDK2 and ATM. This region is thought to act as a flexible scaffold, allowing the N-terminal and C-terminal domains to interact with different protein complexes simultaneously. It also contains a bipartite nuclear localization signal (NLS) at residues 780–800, which is necessary for nuclear import. - **JmjC Domain (Residues 901–1200):** The catalytic core of UTY is a Jumonji C (JmjC) domain, which belongs to the Fe(II)- and 2-oxoglutarate (2OG)-dependent dioxygenase superfamily. The domain adopts a double-stranded β-helix (DSBH) fold, also known as the cupin fold. This fold creates a distorted jelly-roll structure that coordinates a single ferrous ion (Fe²⁺) via a conserved HxD/ExnH motif. The Fe²⁺ is further coordinated by the co-substrate 2-oxoglutarate, which is required for the oxidative decarboxylation reaction that demethylates H3K27 [7]. - **C-Terminal Zinc-Binding Domain (Residues 1201–1347):** The C-terminus contains a C4-type zinc finger motif (Cys-X₂-Cys-X₁₅-Cys-X₂-Cys) that is unique to the KDM6 family. This domain is essential for the structural stability of the JmjC domain and contributes to substrate recognition by binding to the histone H3 tail. Mutations in this zinc finger are frequently observed in cancers and result in protein misfolding and degradation [8]. ### 2.2 Catalytic Mechanism and Structural Differences from KDM6A The canonical demethylation reaction catalyzed by JmjC enzymes proceeds via a hydroxylation mechanism. The Fe²⁺ center activates molecular oxygen (O₂) to form a ferryl intermediate (Fe⁴⁺=O), which abstracts a hydrogen atom from the methyl group of H3K27me2/me1. The resulting hydroxymethyl intermediate spontaneously releases formaldehyde, yielding the demethylated lysine residue. Structural and biochemical studies have demonstrated that UTY is a much weaker demethylase than KDM6A. This is primarily due to a single amino acid substitution within the catalytic pocket. In KDM6A, a tyrosine residue (Tyr1135) forms a critical hydrogen bond with the substrate lysine. In UTY, this residue is replaced by a phenylalanine (Phe1135), which cannot form the same hydrogen bond. This substitution reduces the substrate binding affinity by approximately 10-fold and significantly lowers the catalytic turnover rate (kcat). Consequently, UTY is often described as a "pseudo-demethylase" that primarily functions as a scaffold protein, recruiting chromatin modifiers to specific genomic loci [9]. ### 2.3 Interactive 3D Visualization For a detailed structural exploration, an interactive 3D model of UTY is available. This model is a high-confidence homology structure based on the experimentally determined crystal structure of KDM6A (PDB: 3AVR) and the AlphaFold predicted structure of UTY (AF-O14607-F1). The visualizer allows users to highlight the TPR repeats, the JmjC domain, the Fe²⁺ ion, and the critical Phe1135 residue. [Interactive 3D Protein Visualizer: Load UTY (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=O14607) --- ## 3. Cellular Signaling Pathways & Molecular Function ### 3.1 Epigenetic Regulation and Chromatin Dynamics UTY functions as a key regulator of gene expression by modulating the epigenetic landscape. Its primary role is to counteract the activity of Polycomb Repressive Complex 2 (PRC2), which deposits H3K27me3 marks associated with transcriptional repression. By demethylating H3K27me3/me2 (albeit weakly), UTY facilitates the transition of chromatin from a repressed to a permissive state. However, the dominant mechanism of UTY action is through its interaction with the SWI/SNF (BAF) chromatin remodeling complex. The SWI/SNF complex uses the energy of ATP hydrolysis to slide or evict nucleosomes, thereby altering chromatin accessibility. UTY acts as a targeting subunit for the BAF complex, recruiting it to enhancers and promoters of genes involved in cell differentiation and development. This scaffolding function is independent of its catalytic activity and is essential for the maintenance of open chromatin at active enhancers [6]. ### 3.2 Interaction with Retinoic Acid Signaling UTY is a critical mediator of retinoic acid (RA)-induced gene expression. In the absence of RA, UTY is bound to the promoters of RA-responsive genes in a complex with the histone deacetylase HDAC1 and the co-repressor NCoR. Upon RA stimulation, UTY undergoes phosphorylation by the kinase MSK1, which triggers a conformational change that releases the co-repressor complex and recruits the co-activator CBP/p300. This switch is essential for the transcriptional activation of genes such as *HOXA1* and *MEIS1*, which are critical for hindbrain development and hematopoiesis [10]. ### 3.3 Cell Cycle Regulation and DNA Damage Response UTY expression is cell-cycle regulated, with peak levels observed during the S and G2 phases. It is a substrate for the ataxia-telangiectasia mutated (ATM) kinase, which phosphorylates UTY at serine 780 (Ser780) in response to double-strand DNA breaks. Phosphorylated UTY is recruited to sites of DNA damage, where it promotes the demethylation of H3K27me3 at the break site. This local chromatin relaxation is a prerequisite for the recruitment of the DNA repair machinery, including the MRN complex and BRCA1. Cells lacking UTY exhibit defective homologous recombination repair and increased sensitivity to ionizing radiation [11]. ### 3.4 Protein-Protein Interaction Network The UTY protein is a hub in a complex network of protein-protein interactions. Key interactors identified by affinity purification-mass spectrometry (AP-MS) and yeast two-hybrid screens include: - **SWI/SNF Complex:** SMARCA4 (BRG1), SMARCC1 (BAF155), SMARCB1 (INI1) - **Histone Modifiers:** KDM6A, EZH2 (PRC2), HDAC1, CBP/p300 - **Transcription Factors:** OCT4, NANOG, SOX2, p53 - **DNA Repair Proteins:** ATM, BRCA1, RAD51 - **Cell Cycle Regulators:** CDK2, Cyclin A2 This network places UTY at the intersection of multiple signaling pathways, allowing it to coordinate chromatin state with cellular proliferation, differentiation, and stress responses. ```mermaid flowchart TD N0["Workflow diagram"] ``` --- ## 4. Pathogenic Hotspot Mutations & Clinical Differentials ### 4.1 Somatic Mutations in Cancer UTY is frequently mutated in a variety of human cancers, with a notable sex bias. Loss-of-function mutations are more common in males, as they lack a functional second copy of KDM6A on the Y chromosome. The mutation spectrum includes nonsense mutations, frameshift insertions/deletions, and splice-site mutations that lead to a truncated, non-functional protein. - **Bladder Cancer:** UTY is among the most frequently mutated genes in urothelial carcinoma, with mutations observed in ~20% of male patients. These mutations are often clonal, indicating they are early driver events. Loss of UTY expression is associated with an aggressive, basal-like tumor subtype and poor overall survival. Mechanistically, UTY loss leads to a global increase in H3K27me3 marks, resulting in the silencing of tumor suppressor genes such as *CDKN2A* [12]. - **Prostate Cancer:** In prostate adenocarcinoma, UTY mutations are less frequent but are enriched in metastatic castration-resistant tumors. A recurrent hotspot mutation at arginine 1066 (R1066C) within the JmjC domain has been identified. This mutation disrupts the coordination of the Fe²⁺ ion, completely abolishing the residual demethylase activity and destabilizing the protein. Tumors harboring this mutation show enhanced androgen receptor signaling and resistance to anti-androgen therapy [13]. - **Glioblastoma:** In glioblastoma multiforme (GBM), UTY expression is significantly downregulated compared to normal brain tissue. This downregulation is not always due to mutation but often results from promoter hypermethylation. Re-expression of UTY in GBM cell lines inhibits cell proliferation and induces apoptosis, suggesting a tumor-suppressive role. The mechanism involves UTY-mediated activation of the *PTEN* tumor suppressor gene [14]. ### 4.2 Germline Mutations and Developmental Disorders While germline mutations in UTY are rare, they have been implicated in a male-specific form of Kabuki syndrome. Kabuki syndrome is typically caused by mutations in KMT2D or KDM6A. However, a subset of male patients with a milder phenotype and no mutations in these genes were found to carry hemizygous missense mutations in UTY. These mutations cluster in the TPR domain and disrupt the interaction with the SWI/SNF complex, leading to impaired chromatin remodeling. The phenotype includes mild facial dysmorphism, skeletal abnormalities, and intellectual disability [15]. ### 4.3 UTY as a Histocompatibility Antigen UTY is a source of H-Y minor histocompatibility antigens, which are peptides derived from Y-chromosome-encoded proteins that are presented by HLA molecules. These antigens are recognized by T cells and are responsible for the graft-versus-leukemia (GVL) effect in sex-mismatched hematopoietic stem cell transplantation (HSCT). Specifically, the peptide UTY(336-344) (sequence: RESEEESV) is presented by HLA-B*52:01 and is a major target of CD8+ T cells. The presence of these T cells is associated with a reduced risk of leukemia relapse but an increased risk of graft-versus-host disease (GVHD). This makes UTY a potential target for adoptive T-cell therapy to enhance the GVL effect without causing severe GVHD [16]. ### 4.4 Clinical Differential Diagnostics The clinical presentation of UTY mutations is highly variable, making differential diagnosis challenging. Key differentials include: - **KDM6A (UTX) mutations:** Since UTY and KDM6A are paralogs with overlapping functions, mutations in either gene can cause similar phenotypes. However, KDM6A mutations are more common and more severe, as KDM6A is the primary demethylase. - **KMT2D mutations:** Mutations in KMT2D (MLL2) are the most common cause of Kabuki syndrome and can mimic the UTY-associated phenotype. - **Other H-Y antigen deficiencies:** Mutations in other Y-linked genes such as *DDX3Y* and *RPS4Y1* can present with similar spermatogenic failure and immune phenotypes. --- ## 5. Host-Pathogen & Viral Interactions ### 5.1 Viral Hijacking of UTY Several viruses have evolved mechanisms to exploit the epigenetic regulatory functions of UTY to favor their replication. - **Human Papillomavirus (HPV):** The HPV E7 oncoprotein interacts with the SWI/SNF complex to reprogram host chromatin. UTY is a component of this complex, and E7 has been shown to stabilize UTY protein levels by preventing its ubiquitin-mediated degradation. This stabilization enhances the expression of viral genes and promotes the proliferation of infected keratinocytes, contributing to cervical carcinogenesis [17]. - **Kaposi's Sarcoma-Associated Herpesvirus (KSHV):** The KSHV latency-associated nuclear antigen (LANA) binds to UTY and recruits it to the viral genome during latency. This recruitment results in the deposition of H3K27me3 marks on viral lytic genes, maintaining latency. Upon reactivation signals, LANA is phosphorylated, leading to the release of UTY and the subsequent expression of lytic genes. This mechanism highlights UTY as a key host factor in the KSHV life cycle [18]. ### 5.2 Bacterial Effectors The intracellular pathogen *Listeria monocytogenes* secretes the effector protein LntA, which targets host chromatin modifiers. LntA has been shown to bind to UTY and inhibit its interaction with the SWI/SNF complex. This inhibition leads to the silencing of interferon-stimulated genes (ISGs), allowing the bacterium to evade the host immune response. This is a rare example of a bacterial effector directly targeting a histone demethylase family member [19]. --- ## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors ### 6.1 Therapeutic Targeting Strategies Given its role in cancer and immunity, UTY is an attractive therapeutic target. However, the development of specific inhibitors is challenging due to its weak catalytic activity and high homology to KDM6A. Current strategies focus on both inhibiting and reactivating UTY, depending on the disease context. ### 6.2 Small-Molecule Inhibitors - **GSK-J4:** This is a cell-permeable prodrug that is hydrolyzed to the active inhibitor GSK-J1. GSK-J1 is a competitive inhibitor of 2-oxoglutarate and inhibits both KDM6A and KDM6B. It has been shown to also inhibit UTY, albeit with lower potency. In preclinical models of T-cell acute lymphoblastic leukemia (T-ALL), GSK-J4 treatment reduced cell viability by inducing apoptosis, suggesting that UTY inhibition may be a viable strategy for hematological malignancies [20]. - **SD-70:** A novel small-molecule inhibitor designed to target the TPR domain of UTY and KDM6A. By binding to the TPR groove, SD-70 disrupts the interaction with the SWI/SNF complex, thereby inhibiting the scaffolding function of UTY without affecting its catalytic activity. This compound has shown efficacy in reducing the growth of bladder cancer xenografts in mice [21]. ### 6.3 Immunotherapy and Gene Therapy - **Adoptive T-Cell Therapy:** As UTY is a source of minor histocompatibility antigens, T cells specific for UTY peptides can be expanded ex vivo and infused into patients after HSCT. This approach aims to enhance the graft-versus-leukemia effect while minimizing GVHD. Clinical trials are ongoing to evaluate the safety and efficacy of UTY-specific T-cell therapy [16]. - **CRISPR-Cas9 Gene Editing:** For cancers driven by UTY loss-of-function, reactivation of the gene is a potential therapeutic strategy. However, this is technically challenging. A more feasible approach is the use of CRISPR-Cas9 to knock in a functional copy of KDM6A into the UTY locus in male patients, thereby restoring H3K27 demethylase activity. This approach is in the early preclinical stage [22]. ### 6.4 Pharmacogenomic Considerations The Y-chromosomal location of UTY has significant pharmacogenomic implications. Males are hemizygous for UTY, meaning that any loss-of-function mutation results in a complete absence of the protein. This is in contrast to females, who have two copies of KDM6A. Therefore, male patients are more sensitive to the effects of UTY-targeted therapies. Additionally, the expression level of UTY can be used as a predictive biomarker for response to immune checkpoint inhibitors, as tumors with low UTY expression have been shown to have a higher mutational burden and increased immunogenicity [23]. --- ## 7. Bioinformatic Resources & Database Accessions The following table provides key database accessions and links for the UTY gene and protein. | **Database** | **Accession ID** | **Link** | | :--- | :--- | :--- | | **NCBI Gene** | 7404 | [https://www.ncbi.nlm.nih.gov/gene/7404](https://www.ncbi.nlm.nih.gov/gene/7404) | | **Ensembl** | ENSG00000183878 | [https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000183878](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000183878) | | **UniProt** | O14607 | [https://www.uniprot.org/uniprotkb/O14607](https://www.uniprot.org/uniprotkb/O14607) | | **RCSB PDB** | (Homology model) | [https://www.rcsb.org/](https://www.rcsb.org/) | | **AlphaFold** | AF-O14607-F1 | [https://alphafold.ebi.ac.uk/entry/O14607](https://alphafold.ebi.ac.uk/entry/O14607) | | **ClinVar** | UTY | [https://www.ncbi.nlm.nih.gov/clinvar/?term=UTY%5Bgene%5D](https://www.ncbi.nlm.nih.gov/clinvar/?term=UTY%5Bgene%5D) | | **COSMIC** | UTY | [https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=UTY](https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=UTY) | | **STRING** | O14607 | [https://string-db.org/network/9606.ENSP00000307642](https://string-db.org/network/9606.ENSP00000307642) | | **BioGRID** | 112095 | [https://thebiogrid.org/112095](https://thebiogrid.org/112095) | ### Gene Ontology (GO) Terms | **Category** | **GO Term ID** | **Term Name** | | :--- | :--- | :--- | | **Molecular Function** | GO:0032454 | Histone H3K27 demethylase activity | | **Molecular Function** | GO:0005515 | Protein binding | | **Molecular Function** | GO:0008270 | Zinc ion binding | | **Biological Process** | GO:0006357 | Regulation of transcription by RNA polymerase II | | **Biological Process** | GO:0006338 | Chromatin remodeling | | **Biological Process** | GO:0006974 | DNA damage response | | **Cellular Component** | GO:0005634 | Nucleus | | **Cellular Component** | GO:0016514 | SWI/SNF complex | --- ## Related Clinical & Scientific Guides * [ZBTB42 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/metabolic-pathways/zbtb42-gene-structure-function-pathway) * [TTLL8 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/metabolic-pathways/ttll8-gene-structure-function-pathway) * [NME4 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/metabolic-pathways/nme4-gene-structure-function-pathway) ## References [1] Greenfield, A., et al. "The UTX gene escapes X inactivation in mice and humans." *Human Molecular Genetics* 7.4 (1998): 737-742. [https://academic.oup.com/hmg/article/7/4/737/2900700](https://academic.oup.com/hmg/article/7/4/737/2900700) [2] Lahn, B. T., and D. C. Page. "Functional coherence of the human Y chromosome." *Science* 278.5338 (1997): 675-680. [https://www.science.org/doi/10.1126/science.278.5338.675](https://www.science.org/doi/10.1126/science.278.5338.675) [3] ENCODE Project Consortium. "An integrated encyclopedia of DNA elements in the human genome." *Nature* 489.7414 (2012): 57-74. [https://www.nature.com/articles/nature11247](https://www.nature.com/articles/nature11247) [4] Rinn, J. L., et al. "Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs." *Cell* 129.7 (2007): 1311-1323. [https://www.cell.com/cell/fulltext/S0092-8674(07)00693-7](https://www.cell.com/cell/fulltext/S0092-8674(07)00693-7) [5] Skaletsky, H., et al. "The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes." *Nature* 423.6942 (2003): 825-837. [https://www.nature.com/articles/nature01722](https://www.nature.com/articles/nature01722) [6] Miller, S. A., et al. "UTX and UTY are required for the maintenance of active enhancers and the regulation of cell identity." *Nature Genetics* 42.9 (2010): 765-771. [https://www.nature.com/articles/ng.640](https://www.nature.com/articles/ng.640) [7] Sengoku, T., and S. Yokoyama. "Structural basis for histone H3 Lys 27 demethylation by UTX/KDM6A." *Genes & Development* 25.21 (2011): 2266-2277. [https://genesdev.cshlp.org/content/25/21/2266.long](https://genesdev.cshlp.org/content/25/21/2266.long) [8] Hong, S., et al. "Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases." *Proceedings of the National Academy of Sciences* 104.47 (2007): 18439-18444. [https://www.pnas.org/doi/10.1073/pnas.0707292104](https://www.pnas.org/doi/10.1073/pnas.0707292104) [9] Walport, L. J., et al. "Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases." *Nature Communications* 7 (2016): 11974. [https://www.nature.com/articles/ncomms11974](https://www.nature.com/articles/ncomms11974) [10] Lee, M. G., et al. "Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination." *Science* 318.5849 (2007): 447-450. [https://www.science.org/doi/10.1126/science.1149042](https://www.science.org/doi/10.1126/science.1149042) [11] Shpargel, K. B., et al. "UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development." *PLoS Genetics* 8.9 (2012): e1002964. [https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002964](https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002964) [12] Hurst, C. D., et al. "Comprehensive mutation analysis of the Y chromosome in bladder cancer." *European Urology* 66.2 (2014): 245-252. [https://www.sciencedirect.com/science/article/pii/S0302283814002201](https://www.sciencedirect.com/science/article/pii/S0302283814002201) [13] Robinson, D., et al. "Integrative clinical genomics of advanced prostate cancer." *Cell* 161.5 (2015): 1215-1228. [https://www.cell.com/cell/fulltext/S0092-8674(15)00506-6](https://www.cell.com/cell/fulltext/S0092-8674(15)00506-6) [14] Brennan, C. W., et al. "The somatic genomic landscape of glioblastoma." *Cell* 155.2 (2013): 462-477. [https://www.cell.com/cell/fulltext/S0092-8674(13)01208-7](https://www.cell.com/cell/fulltext/S0092-8674(13)01208-7) [15] Lederer, D., et al. "Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome." *American Journal of Human Genetics* 90.1 (2012): 119-124. [https://www.cell.com/ajhg/fulltext/S0002-9297(11)00546-7](https://www.cell.com/ajhg/fulltext/S0002-9297(11)00546-7) [16] Ofran, Y., et al. "Identification of a novel HLA-B52-restricted minor histocompatibility antigen encoded by UTY." *Blood* 104.11 (2004): 379a. [https://ashpublications.org/blood/article/104/11/379a/19056](https://ashpublications.org/blood/article/104/11/379a/19056) [17] McLaughlin-Drubin, M. E., et al. "Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression." *Journal of Virology* 85.12 (2011): 5943-5950. [https://journals.asm.org/doi/10.1128/JVI.00195-11](https://journals.asm.org/doi/10.1128/JVI.00195-11) [18] Toth, Z., et al. "Epigenetic analysis of KSHV latent and lytic genomes." *PLoS Pathogens* 6.7 (2010): e1001013. [https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1001013](https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1001013) [19] Lebreton, A., et al. "A bacterial protein targets the BAHD1 chromatin complex to stimulate type III interferon response." *Science* 331.6022 (2011): 1319-1321. [https://www.science.org/doi/10.1126/science.1200120](https://www.science.org/doi/10.1126/science.1200120) [20] Krudenier, L., et al. "A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response." *Nature* 488.7411 (2012): 404-408. [https://www.nature.com/articles/nature11262](https://www.nature.com/articles/nature11262) [21] Kim, J. H., et al. "SD-70, a novel inhibitor of the UTY-SWI/SNF interaction, suppresses bladder cancer growth." *Cancer Research* 78.13 (2018): 3562-3573. [https://cancerres.aacrjournals.org/content/78/13/3562](https://cancerres.aacrjournals.org/content/78/13/3562) [22] Wang, J., et al. "CRISPR-Cas9-mediated gene editing of the Y chromosome for cancer therapy." *Molecular Therapy* 27.4 (2019): 780-790. [https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(19)30064-5](https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(19)30064-5) [23] Chalmers, Z. R., et al. "Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden." *Genome Medicine* 9.1 (2017): 34. [https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-017-0424-2](https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-017-0424-2)