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    • br To explore further the functional

    2021-10-20


    To explore further the functional impact of the similarity of the UTY and KDM6A proteins, the FANTOM5 human dataset was analysed to determine whether or not the genes were expressed at the same time in the same tissues (which would suggest that they are controlled by the same regulators) or with opposite expression patterns (suggesting that there is a mechanism to regulate the combined level of the mRNA/proteins within a cell). An initial survey showed that many samples did not express UTY. However, all testes and prostate samples did express UTY, suggesting that those where UTY was not detected were from female donors. This was validated where possible using the sample metadata (http://fantom.gsc.riken.jp/5/sstar/Main_Page). KDM6A and UTY expression levels (TPM) were strongly positively correlated across the data set of male samples (Pearson's correlation r = 0.720, N = 517; Fig. 3A). These results show that UTY probably does not compensate for low KDM6A expression, since when there was high UTY expression, there was also high KDM6A expression, consistent with co-regulation of the two genes across all cell types, as previously reported for mouse brain [13]. A strong correlation was found in the subset of samples from tissues and primary cell lines (r = 0.728, N = 439; Fig. 3B). The association was much weaker when only cancerous samples were included (r = 0.322, N = 78; Fig. 3C), consistent with the high level of mutation of KDM6A (and to some extent UTY) in cancer [20] and suggesting that some of these mutations affect the regulatory motifs controlling the binding of transcription factors. KDM6B expression did not have a high correlation with UTY or KDM6A expression (r = 0.469, N = 1829 with KDM6A and r = 0.261, N = 517 with UTY), indicating that it is regulated independently and has a distinct expression pattern compared with KDM6A and UTY. To understand the potential co-regulation of UTY and KDM6A, an analysis of transcription factor (TF) motifs was performed, using Harmonizome (https://amp.pharm.mssm.edu/Harmonizome/) [84], a relational database of functional associations between genes and proteins, and their attributes. Different predicted TF peptide yy for KDM6A, UTY and KDM6B were identified. Several databases for TF binding sites were used (TRANSFAC, JASPAR, CHEA and ENCODE [[85], [86], [87], [88], [89], [90]]). TRANSFAC and JASPAR predict TF binding using known binding site motifs, whereas CHEA and ENCODE use ChIP-seq data. The TRANSFAC dataset also provided curated data, which were manually selected from low-throughput or high-throughput TF functional studies. A number of TF binding sites appeared common to KDM6A and UTY, especially in the TRANSFAC curated dataset, where all 10 UTY TF were shared by KDM6A. Fewer TF sites were shared between KDM6A and KDM6B or UTY and KDM6B. In the ChIP-seq based data the UTY promoter did not have as many TF binding sites as the other two. In both CHEA and ENCODE datasets KDM6A and KDM6B had a number of TF binding sites in common, unlike UTY. The ENCODE dataset also showed 32 different TF sites which were common to all three gene promoters. A summary of these results is presented in Supplementary Fig. 3. Although UTY may serve a separate male specific function, for example in testes, it appears to be expressed in a wide range of cell types (as shown in the BioGPS dataset and FANTOM5 data). The findings presented in this section suggest that in general KDM6A and UTY have shared regulation, which may allow for survival of males by compensating for the haploinsufficiency of KDM6A. In contrast, KDM6B appears to have very different regulation and showed little redundancy with KDM6A and UTY, indicating that this protein likely has an independent role.
    Clinical significance of KDM6A and UTY X chromosome genes with a Y chromosome homologue (many of them coding for chromatin-modifying enzymes including KDM6A) are needed for proper gene regulation and are potentially sensitive to altered dosage [17]. In particular, X chromosome genes that escape X inactivation may be subject to a dose response which leaves males haploinsufficient, unless the Y homologue has similar activity. Abnormal modification of histone proteins has been associated with multiple diseases in humans and animal models [91]. This means that a range of clinical conditions are likely to be associated with abnormalities of KDM6A. The analysis of KDM6A and UTY gene expression (Section 4) suggests that the two genes are co-regulated and that UTY might compensate in males for the single copy of KDM6A.