In Kdm c germline and forebrain conditional knockout mice

In Kdm5c germline and forebrain conditional knockout mice, RNA sequencing showed the upregulation of a large set of genes, suggesting that Kdm5c functions primarily as a transcriptional repressor [,]. While no changes in global H3K4me3 levels were observed in the knockout neurons, there were thousands of differentially methylated peaks, primarily exhibiting local increases in H3K4me3. De novo H3K4me3 peaks were most common at intergenic regions that are marked by H3K4me1 in wildtype, suggesting that enhancers more than promoters are particularly sensitive to the loss of Kdm5c []. Despite the fact that Kdm5c is broadly bound at the promoters of expressed genes, genes that showed the highest induction of expression and the greatest increase in H3K4me3 at their promoters in the absence of Kdm5c were those that were lowly expressed in wildtype [,]. These data suggest that Kdm5c is primarily required for fine-tuning gene expression by suppressing the accumulation of H3K4me3 at active regulatory elements. Notably, although most ID-associated mutations in KDM5C disrupt the histone demethylase activity of this enzyme, a point mutant was recently identified that neither disrupts protein expression or enzyme activity (Figure 2c) []. Thus, Kdm5c may also have non-enzymatic activities that contribute to Amphotericin B development.
Other HDMs in neurodevelopmental disorders In addition to the HDMs highlighted here, many other HDMs are expressed in neurons [29], and mutations in several of these have been found in neurodevelopmental syndromes, highlighting their importance human brain development. For example, microdeletion of 12a24.31, which is a genomic region that contains both KDM2B and the histone methyltransferases SETD1B, causes an ID syndrome [40], and multiple mutations in the H3K9 demethylase JMJD1C (KDM3C) were found upon targeted resequencing of a set of patients clinically diagnosed with ASD, ID, or Rett Syndrome without an identified genetic defect [41]. The most common forms of ID are X-linked, adding urgency to the study of HDMs that localize to the X chromosome. The H3K9/H4K20 demethylase PHF8 (KDM7B) is associated with both syndromic and non-syndromic forms of X-linked ID [42]. Chen et al. [] generated Phf8 knockout mice as an animal model of these disorders and showed the knockouts exhibited learning and memory impairments in behavioral assays and long-term potentiation (LTP) deficits in slice electrophysiology []. A bioinformatics approach suggested the upregulation of the mTOR pathway in these mice and, interestingly, an inhibitor of mTOR (rapamycin) was able to rescue the learning/memory as well as LTP defects in these mice. Tang et al. [44] conducted a similar study on a different X chromosome HDM, Kdm6a (Utx) [44]. They generated forebrain-specific Kdm6a knockout mice, which exhibited deficits in learning and memory, as well as morphological and functional abnormalities of hippocampal synapses [44]. Among the genes downregulated in the conditional knockouts, the authors focused on the serotonin receptor Htr5b and showed that overexpression could rescue dendritic defects in Kdm6a knockout neurons. These findings have potential relevance for the cognitive symptoms in Kabuki Syndrome, a congenital craniofacial disorder, for which KDM6A mutations are one genetic cause. Although conditional genetic deletion of Kdm6a in the neural crest of mice recapitulates dysmorphic features of Kabuki syndrome, craniofacial development is mostly independent of the demethylase activity of Kdm6a because mice bearing a demethylase-dead knockin mutation of Kdm6a have normal facial morphology []. These data reiterate that the connections between the biological and biochemical functions of the HDMs remain to be fully explored, and they show that understanding the relevant actions of the HDMs in neurons will be required to develop meaningful potential therapeutics.
Concluding remarks