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  • br Conclusions H K demethylases perform an important

    2022-09-29


    Conclusions H3K27 demethylases perform an important catalytic function in mediating change in gene expression, whether it is during cell differentiation or activation, because they remove repressive marks from histones which opens the chromatin and facilitates transcription. The number of publications on KDM6A listed in PubMed (https://www.ncbi.nlm.nih.gov/pubmed) has increased annually from 1 in 2010 to 55 in 2018 and 30 in the first quarter of 2019. In contrast, UTY has received very little attention with 4 papers in 2010 and 7 in 2018. In this review, KDM6A and UTY were analysed in detail to observe the level of similarity between these two genes, and assess the importance of UTY in cells. We have shown that UTY is co-regulated with KDM6A. It is proposed that UTY compensates for KDM6A in eutherian males and is responsible for the association between the loss of the Y chromosome and poor prognosis in a range of cancers. Given its role in oocyte maturation, development and carcinogenesis, KDM6A is a target for treatment of cancer and potentially infertility, but the contribution of UTY to maintenance of H3K27 demethylation homeostasis should not be neglected.
    Funding IG was supported by a scholarship from the Lady Tata Memorial Trust, London, United Kingdom. KMS receives support from the Mater Research Foundation, Brisbane, Australia. Some of this work was carried out at the Roslin Institute, University of Edinburgh, United Kingdom, which receives strategic core funding from the Biotechnology and Biological Sciences Research Council of the United Kingdom (BB/J004235/1, BB/E/D/20211552, BB/J004227/1, BB/E/D/20231762).
    Introduction Myelopoiesis is the process of producing all types of myeloid JNJ-38877605 receptor including granulocytes and monocytes/macrophages from stem and progenitor cells. Myeloid cells are critical effectors and regulators of tissue regeneration, innate and adaptive immune response [1]. Malfunction or dysregulation of myelopoiesis is tightly associated with various human blood diseases including acute myeloid leukemia (AML) [2]. Previous studies have illustrated the essential role of several transcription factors for normal vertebrate myelopoiesis, including Spi1, C/ebpα, Gcsfr, Irf8, and Gfi1 [[3], [4], [5], [6], [7]]. However, the orchestrated regulatory programs, consisting of both transcriptional and epigenetic controls during normal myeloid development, remain unclear. Recently, zebrafish has emerged as an excellent vertebrate animal model to study the development of myelopoiesis [[8], [9], [10]]. Similar to mammals, zebrafish has most of the myeloid cell types including neutrophil, monocyte, eosinophil, mast cell and dendritic cell [[11], [12], [13], [14], [15]]. In a developing vertebrate embryo, hematopoiesis consists of two successive waves, termed primitive hematopoiesis and definitive hematopoiesis [9]. In zebrafish, the primitive hematopoiesis takes place in the anterior lateral plate mesoderm (ALPM) and intermediate cell mass (ICM), producing primitive myeloid cells and erythrocytes, respectively [16]. On the other hand, definitive hematopoiesis occurs at the ventral wall of dorsal aorta at a site called aorta-gonad-mesonephros (AGM) around 28 hours post-fertilization (hpf) [17]. By 48 hpf, the AGM-derived hematopoietic stem/progenitor cells (HSPCs) migrate to the caudal hematopoietic tissue (CHT, equivalent to the mammalian fetal liver) for rapid lineage expansion and differentiation [18,19]. Alternatively, the erythromyeloid progenitors (EMPs) that arise autonomously in the posterior blood island (PBI) between 24 and 36 hpf can also generate definitive erythroid and myeloid colonies [20]. The important role that histone methylation plays during transcriptional regulation of gene expression in cell differentiation and proliferation has been long recognized [21]. Trimethylated histone H3 at lysine 4 (H3K4me3) marks transcriptionally active chromatin states, whereas trimethylated histone H3 at lysine 27 (H3K27me3) marks transcriptionally repressive chromatin states. Jumonji domain-containing protein D3 (Jmjd3, also named Kdm6b) is a member of the H3K27me3/2-specific demethylase family that promotes gene transcription by acting as a rival of the Polycomb repressive complex 2 (PRC2) [22,23]. Studies using embryonic stem cells suggest that Jmjd3 is required for the development of all three germ layers [[24], [25], [26]], Jmjd3 accelerates the specification of pluripotent cells by removing H3K27me3 barriers [27]. It has also been shown that Jmjd3 function is necessary for the differentiation and proliferation of cells in different tissues, such as neurons, epidermal cells, cardiac cells, M2 macrophages and T cells [23,25,[28], [29], [30]]. However, the in vivo function of Jmjd3 in myeloid lineage development remains to be determined.