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      AZFa candidate gene UTY and its X homologue UTX are expressed in human germ cells

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          Summary

          The Ubiquitous Transcribed Y ( UTY a.k.a. KDM6C) AZFa candidate gene on the human Y chromosome and its paralog on the X chromosome, UTX (a.k.a. KDM6A), encode a histone lysine demethylase removing chromatin H3K27 methylation marks at genes transcriptional start sites for activation. Both proteins harbour the conserved Jumonji C (JmjC) domain, functional in chromatin metabolism, and an extended N-terminal tetratricopeptide repeat (TPR) block involved in specific protein interactions. Specific antisera for human UTY and UTX proteins were developed to distinguish the expression of both proteins in human germ cells by immunohistochemical experiments on appropriate tissue sections. In the male germ line, UTY was expressed in the fraction of A spermatogonia located at the basal membrane, probably including spermatogonia stem cells. UTX expression was more spread in all spermatogonia and in early spermatids. In female germ line, UTX expression was found in the primordial germ cells of the ovary. UTY was also expressed during fetal male germ cell development, whereas UTX expression was visible only at distinct gestation weeks. Based on these results and the conserved neighboured location of UTY and DDX3Y in Yq11 found in mammals of distinct lineages, we conclude that UTY, such as DDX3Y, is part of the Azoospermia factor a (AZFa) locus functioning in human spermatogonia to support the balance of their proliferation-differentiation rate before meiosis. Comparable UTY and DDX3Y expression was also found in gonadoblastoma and dysgerminoma cells found in germ cell nests of the dysgenetic gonads of individuals with disorders of sexual development and a Y chromosome in karyotype (DSD-XY). This confirms that AZFa overlaps with GBY , the Gonadoblastoma susceptibility Y locus, and includes the UTY gene.

          Lay summary

          AZFa Y genes are involved in human male germ cells development and support gonadoblastoma (germ cell tumour precursor cells) in the aberrant germ cells of the gonads of females with genetic disorders of sexual development. The AZFa UTY gene on the male Y chromosome is equivalent to UTX on the female X chromosome. These genes are involved in removing gene regulators to enable activation of other genes (i.e. removal of histone methylation known as epigenetic modifications). We wanted to learn the function of UTY and UTX in developing sperm and eggs in human tissues and developed specific antibodies to detect both proteins made by these genes. Both UTY and UTX proteins were detected in adult and fetal sperm precursor cells (spermatogonia). UTX was detected in egg precursor cells (primordial germ cells). UTY was detected in gonadoblastoma and dysgerminoma tumour cells (germ cell tumours originating from genetic disorders of sexual development due to having a Y chromosome). Based on our study, we conclude that UTY is not only part of AZFa, but also of GBY the overlapping gonadoblastoma susceptibility Y region.

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          Most cited references46

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          TPR proteins: the versatile helix.

          Tetratrico peptide repeat (TPR) proteins have several interesting properties, including their folding characteristics, modular architecture and range of binding specificities. In the past five years, many 3D structures of TPR domains have been solved, revealing at a molecular level the versatility of this basic fold. Here, we discuss the structure of TPRs and highlight the diversity of arrangements and functions that are associated with these ubiquitous domains. Genomic analyses of the distribution of TPR domains are presented along with implications for protein engineering.
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            Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination.

            Methylation of histone H3 lysine 27 (H3K27) is a posttranslational modification that is highly correlated with genomic silencing. Here we show that human UTX, a member of the Jumonji C family of proteins, is a di- and trimethyl H3K27 demethylase. UTX occupies the promoters of HOX gene clusters and regulates their transcriptional output by modulating the recruitment of polycomb repressive complex 1 and the monoubiquitination of histone H2A. Moreover, UTX associates with mixed-lineage leukemia (MLL) 2/3 complexes, and during retinoic acid signaling events, the recruitment of the UTX complex to HOX genes results in H3K27 demethylation and a concomitant methylation of H3K4. Our results suggest a concerted mechanism for transcriptional activation in which cycles of H3K4 methylation by MLL2/3 are linked with the demethylation of H3K27 through UTX.
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              Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators

              The human X and Y chromosomes evolved from an ordinary pair of autosomes, but millions of years ago genetic decay ravaged the Y chromosome, and only three percent of its ancestral genes survived. We reconstructed the evolution of the Y chromosome across eight mammals to identify biases in gene content and the selective pressures that preserved the surviving ancestral genes. Our findings indicate that survival was non-random, and in two cases, convergent across placental and marsupial mammals. We conclude that the Y chromosome's gene content became specialized through selection to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of transcription, translation and protein stability. We propose that beyond its roles in testis determination and spermatogenesis, the Y chromosome is essential for male viability, and plays unappreciated roles in Turner syndrome and in phenotypic differences between the sexes in health and disease.
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                Author and article information

                Journal
                Reprod Fertil
                Reprod Fertil
                raf
                Reproduction & Fertility
                Bioscientifica Ltd (Bristol )
                2633-8386
                April 2021
                07 June 2021
                : 2
                : 2
                : 151-160
                Affiliations
                [1 ]Division of Reproduction Genetics, Department of, Gynaecol. Endocrinology & Infertility Disorders , Women Hospital, University of Heidelberg, Germany
                [2 ]Department of Gynaecol. Endocrinology & Infertility Disorders , Women Hospital, University of Heidelberg, Germany
                Author notes
                Correspondence should be addressed to P H Vogt: peter.vogt@ 123456med.uni-heidelberg.de
                Article
                RAF-20-0049
                10.1530/RAF-20-0049
                8812439
                35128450
                265c3cca-acfa-401c-b2a4-19bff0332f38
                © The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                : 23 April 2021
                : 11 May 2021
                Categories
                Research

                uty (kdm6c),utx (kdm6a),human spermatogonia function,azfa locus,gby tumour susceptibility locus

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