Abstract
To enable long-term survival, mammalian adult neurons exhibit unique apoptosis competence. Questions remain as to whether and how neurons globally reprogram the expression of apoptotic genes during development. We systematically examined the in vivo expression of 1923 apoptosis-related genes and associated histone modifications at eight developmental ages of mouse brains. Most apoptotic genes displayed consistent temporal patterns across the forebrain, midbrain, and hindbrain, suggesting ubiquitous robust developmental reprogramming. Although both anti- and pro-apoptotic genes can be up- or downregulated, half the regulatory events in the classical apoptosis pathway are downregulation of pro-apoptotic genes. Reduced expression in initiator caspases, apoptosome, and pro-apoptotic Bcl-2 family members restrains effector caspase activation and attenuates neuronal apoptosis. The developmental downregulation of apoptotic genes is attributed to decreasing histone-3-lysine-4-trimethylation (H3K4me3) signals at promoters, where histone-3-lysine-27-trimethylation (H3K27me3) rarely changes. By contrast, repressive H3K27me3 marks are lost in the upregulated gene groups, for which developmental H3K4me3 changes are not predictive. Hence, developing brains remove epigenetic H3K4me3 and H3K27me3 marks on different apoptotic gene groups, contributing to their downregulation and upregulation, respectively. As such, neurons drastically alter global apoptotic gene expression during development to transform apoptosis controls. Research into neuronal cell death should consider maturation stages as a biological variable.
Highlights
Apoptosis is a ubiquitous regulated cell death pathway in multi-cellular organisms, essential for development, tissue homeostasis, and immune system functions [1]
We comprehensively examined the in vivo temporal regulation of all known apoptosis-related genes in multiple brain regions during mouse development from embryonic day 10.5 (E10.5) to postnatal day 0 (P0)
For the ChIP-seq data, “bed narrowPeak” files containing the peaks of signal enrichment and “bigwig” files containing signal p-values were obtained from Encyclopedia of DNA Elements (ENCODE)
Summary
Apoptosis is a ubiquitous regulated cell death pathway in multi-cellular organisms, essential for development, tissue homeostasis, and immune system functions [1]. With varied expression of apoptosis-related genes ( termed apoptotic genes), neural progenitors and immature and mature post-mitotic neurons can respond differently to apoptotic stimuli. We comprehensively examined the in vivo temporal regulation of all known apoptosis-related genes in multiple brain regions during mouse development from embryonic day 10.5 (E10.5) to postnatal day 0 (P0) This period coincides neurogenesis and neuronal differentiation, and largely excludes gliogenesis. H3K27me deposited by histone methyltransferases (e.g., EZH2) of PRC complexes is a hallmark of polycomb group-mediated transcriptional silencing [39] These histone modifications may serve as an upstream regulation layer to orchestrate the global chronological expression changes of apoptotic genes, but their contributions have not been studied. Knowledge about the developmental reprogramming of the apoptotic gene expression and the underlying regulatory mechanisms is essential to understanding the activity and regulation of the apoptosis pathway in neural development and diseases
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