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  • The strict control of Spi

    2021-09-18

    The strict control of Spi1 expression is critical for proper myeloid cell fate determination, and genetic or epigenetic changes in the Spi1 gene frequently contribute to the leukemogenesis in mice and human. It is has been shown that Spi1 expression is frequently downregulated in human AML patients [61,62]. Likewise, a graded reduction of Spi1 to 20% of the wild type level induces AML in mice [63]. Moreover, Spi1 mutations are found in about 7% of the patients in a survey involving 126 AML patients [64]. In this respect, the H3K4 methyltransferase Mll1 has recently been shown to be able to occupy the regulatory region to activate the transcription of Spi1 [65]. We provide evidence that jmjd3 play a critical role in controlling spi1 expression in zebrafish. Using a whole embryo ChIP-PCR analysis, we found that endogenous H3K27me3 modification was predominantly enriched at the spi1 regulatory region, and Jmjd3 activity was required to prevent a hyper H3K27me3 level at the region. A confirmation by a ChIP-seq analysis in myeloid cell lines and/or purified myeloid CCT241533 hydrochloride australia is necessary and such a genome-wide analysis may also shed light on the regulation of other myeloid factors by the observed JMJD3 activity. However, the mechanism of how jmjd3 is recruited to spi upstream regulator region needs further investigation and remains unknown. Previous studies and our research showed that Jmjd3 is required for the activation of mammalian developmental programs through a demethylation-activity-dependent mechanism [22,[27], [28], [29]]. Interestingly, other groups have demonstrated that Jmjd3 also functions independently of its enzymatic activity [66,67]. Nonetheless, whether the enzymatic activity of Jmjd3 is required for a proper expression of a target gene needs specific experimental verification.
    Transparency document
    Introduction Increasing evidence suggests that the gut microbiota can affect the symptoms of intellectual disability (ID) and autism spectrum disorder (ASD) diseases (Borghi et al., 2017, Caracciolo et al., 2014, Mayer et al., 2014). It is clear that host genes influence the composition of gut microbiota (Wang et al., 2016, Snijders et al., 2016), but the molecular mechanisms that regulate host-commensal microbiota homeostasis in normal and disease states remain largely unknown. Genome-wide association and family studies have identified many genetic contributors to ID and ASD (Shailesh et al., 2016). Loss-of-function mutations in histone demethylases KDM5A, KDM5B, or KDM5C are found in patients with ID and ASD (Fieremans et al., 2015, Martin et al., 2018). KDM5 family proteins are transcriptional regulators that act by demethylating a histone H3K4me3 modification associated with promoters of transcriptionally active genes (Secombe et al., 2007). Consistent with the enzymatic activity of KDM5 proteins in the underlying cause of ID and ASD, many missense mutations in KDM5C reduce demethylase enzymatic activity in vitro (Brookes et al., 2015). Interestingly, KDM5C functions are highly evolutionarily conserved as kdm5c knockout mice exhibit abnormal learning and social behavior (Iwase et al., 2016, Scandaglia et al., 2017, Martin et al., 2018). A fly strain harboring an allele analogous to a disease-causing missense mutation in human KDM5C (kdm5) shows learning and memory defects (Zamurrad et al., 2018). Significantly, flies with this mutation show transcriptional and behavioral defects that are indistinguishable from fly strains lacking KDM5 demethylase activity (Zamurrad et al., 2018), further supporting a critical role for the demethylase activity of KDM5 in behavior. The human genome has four KDM5 paralogs, while the Drosophila genome has a single KDM5 ortholog. Drosophila is a widely accepted model for studying behavior (Ramdya et al., 2017). In addition, Drosophila provides an excellent system in which to study host-microbe interactions because of CCT241533 hydrochloride australia the ease of its genetic and physiological manipulation, as well as its relatively simple microbial community (Han et al., 2017). Accumulating evidence indicates that the Drosophila gut environment is characterized by low bacterial diversity, and the most commonly associated bacterial species are members of the Lactobacillaceae, Enterococcaceae, Acetobacteraceae, and Enterobacteraceae families (Broderick and Lemaitre, 2012, Buchon et al., 2013). These bacteria affect various aspects of Drosophila physiology and gut homeostasis including aging (Clark et al., 2015), gene expression (Broderick et al., 2014), metabolic function (Wong et al., 2014), and social behavior (Venu et al., 2014).