Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity.

Chromatin regulation plays a pivotal role in establishing and maintaining cellular identity and is one of the top pathways disrupted in autism spectrum disorder (ASD). The hippocampus, composed of distinct cell types, is often affected in patients with ASD. However, the specific hippocampal cell types and their transcriptional programs that are dysregulated in ASD are unknown. Using single-nucleus RNA sequencing, we show that the ASD gene, lysine demethylase 5A (KDM5A), regulates the development of specific subtypes of excitatory and inhibitory neurons. We found that KDM5A is essential for establishing hippocampal cell identity by controlling a differentiation switch early in development. Our findings define a role for the chromatin regulator KDM5A in establishing hippocampal cell identity and contribute to the emerging convergent mechanisms across ASD.

The response of Escherichia coli to the alkylating agents chloroacetaldehyde and styrene oxide.

DNA damage is ubiquitous and can arise from endogenous or exogenous sources. DNA-damaging alkylating agents are present in environmental toxicants as well as in cancer chemotherapy drugs and are a constant threat, which can lead to mutations or cell death. All organisms have multiple DNA repair and DNA damage tolerance pathways to resist the potentially negative effects of exposure to alkylating agents. In bacteria, many of the genes in these pathways are regulated as part of the SOS reponse or the adaptive response. In this work, we probed the cellular responses to the alkylating agents chloroacetaldehyde (CAA), which is a metabolite of 1,2-dichloroethane used to produce polyvinyl chloride, and styrene oxide (SO), a major metabolite of styrene used in the production of polystyrene and other polymers. Vinyl chloride and styrene are produced on an industrial scale of billions of kilograms annually and thus have a high potential for environmental exposure. To identify stress response genes in E. coli that are responsible for tolerance to the reactive metabolites CAA and SO, we used libraries of transcriptional reporters and gene deletion strains. In response to both alkylating agents, genes associated with several different stress pathways were upregulated, including protein, membrane, and oxidative stress, as well as DNA damage. E. coli strains lacking genes involved in base excision repair and nucleotide excision repair were sensitive to SO, whereas strains lacking recA and the SOS gene ybfE were sensitive to both alkylating agents tested. This work indicates the varied systems involved in cellular responses to alkylating agents, and highlights the specific DNA repair genes involved in the responses.