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Heterozygous variants in the KAT6A gene encoding the histone lysine acetyltransferase KAT6A (MOZ, MYST3) cause Arboleda-Tham syndrome, a cognitive impairment syndrome. Histone acetylation is generally associated with active gene transcription. Genetic deletion of both alleles of the Kat6a gene in mice causes developmental defects including anterior homeotic transformation, cleft palate, interrupted aortic arch and cardiac septal defects. Loss of KAT6A impairs expression of HOX, DLX and TBX genes, which are essential for body segment identity specification, palate, heart and aortic arch development. However, the effects of loss of KAT6A on chromatin modifications and gene expression in neural cells, which are relevant to normal brain development and function, is still poorly understood. In this study, we used an automated high-throughput chromatin profiling method and RNA sequencing in mouse neural system and progenitor cells to assess the effects of loss of one or two alleles of Kat6a on gene expression, histone acetylation and methylation. We also assessed occupancy by a trithorax group protein and RNA polymerase II. Our data suggests two modes of action for KAT6A: (1) acetylation of histone H3 on lysine 23 at promoters and enhancers and (2) recruitment of the trithorax group protein MLL1 (KMT2A) to promote the expression of developmental genes, including SOX and homeodomain genes. Together, these two functions appear to be required for normal gene expression in neural progenitors and essential for proliferation and neuronal differentiation. Author summaryDuring embryonic development, specific families of transcription factors pattern the early embryo to lay down and define the body and organ structure. However, the mechanisms governing the onset of the expression of these developmental transcription factors in less well understood. KAT6A is thought to promote gene expression by acetylation histone proteins. Here we determine the effects of KAT6A on histone acetylation and gene expression in mouse neural stem and progenitor cells. Our data are relevant for the understanding of pathogenic genetic variants in one allele of the human KAT6A gene, which cause the Arboleda-Tham cognitive impairment syndrome.

BackgroundNeural stem and progenitor cells (NSPCs) are crucial for nervous system development and self-renewal. However, their properties are sensitive to environmental and chemical factors, including chemotherapy agents like cisplatin, an FDA-approved drug used to treat cancer. Cisplatin inhibits DNA replication but can cause side effects such as nephrotoxicity, ototoxicity, and neurotoxicity. While its cytotoxic effects are well understood, the impact of non-cytotoxic cisplatin concentrations on NSPC differentiation remains unclear.MethodsThis study examined how non-cytotoxic cisplatin exposure influences NSPC differentiation and mitochondrial activity, specifically through reactive oxygen species (ROS) generation. Mitochondrial activity was analyzed via tetrazolium salt (MTT) assay, ATP biosynthesis, mitochondrial membrane potential (ΔΨm), biomass, and ROS production. Glycolytic activity was assessed by extracellular acidification and lactate production. Self-renewal capacity and differentiation were measured using flow cytometry and confocal microscopy. Mitochondrial ROS generation was modulated with Mito-TEMPO.ResultsAfter 24 h of non-cytotoxic cisplatin exposure (5 μM), mitochondrial activity increased, as shown by higher MTT conversion, ATP content, ΔΨm, biomass, and ROS levels. Despite a stabilization of mitochondrial activity and ROS production by 72 h, this exposure impaired cell cycle progression, self-renewal, and enhanced differentiation toward neuronal and glial lineages. Inhibition of mitochondrial ROS production reduced neuronal and glial differentiation but did not restore self-renewal or cell cycle progression. A decrease in extracellular acidification and lactate production indicated a shift from glycolysis to mitochondrial respiration.DiscussionEven at subtherapeutic levels, cisplatin disrupts NSPC integrity, driving differentiation through mitochondrial ROS-dependent mechanisms. While inhibiting ROS reduced differentiation, it did not restore NSPC proliferation. These findings highlight the vulnerability of NSPCs to cisplatin, even at doses considered safe. The metabolic shift toward mitochondrial respiration may contribute to this differentiation bias. Future research on co-administration of antioxidant agents during chemotherapy could protect NSPC integrity and mitigate developmental and cognitive risks, especially in neonates exposed via breastfeeding.

Diffuse intrinsic pontine glioma (DIPG), a lethal pediatric cancer driven by H3K27M oncohistones, exhibits aberrant epigenetic regulation and stem-like cell states. Here, we uncover an axis involving H3.3K27M oncohistones, CREB5/ID1, which sustains the stem-like state of DIPG cells, promoting malignancy. We demonstrate that CREB5 mediates elevated ID1 levels in the H3.3K27M/ACVR1WT subtype, promoting tumor growth; while BMP signaling regulates this process in the H3.1K27M/ACVR1MUT subtype. Furthermore, we reveal that H3.3K27M directly enhances CREB5 expression by reshaping the H3K27me3 landscape at the CREB5 locus, particularly at super-enhancer regions. Additionally, we elucidate the collaboration between CREB5 and BRG1, the SWI/SNF chromatin remodeling complex catalytic subunit, in driving oncogenic transcriptional changes in H3.3K27M DIPG. Intriguingly, disrupting CREB5 super-enhancers with ABBV-075 significantly reduces its expression and inhibits H3.3K27M DIPG tumor growth. Combined treatment with ABBV-075 and a BRG1 inhibitor presents a promising therapeutic strategy for clinical translation in H3.3K27M DIPG treatment. Diffuse intrinsic pontine glioma (DIPG) is driven by H3K27M oncohistones, but the exact related mechanisms are poorly understood. Here, the authors identify an H3.3K27M oncohistone-driven CREB5/ID1 axis that promotes transcriptional changes and progression in DIPG, which could represent a potential therapeutic target.