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Erythropoietin Signaling Regulates Key Epigenetic and Transcription Networks in Fetal Neural Progenitor Cells

ABSTRACT: Erythropoietin (EPO) and its receptor are highly expressed in the developing nervous system, and is exogenous EPO therapy is potentially neuroprotective, however the epigenetic and transcriptional changes downstream of EPO signaling in neural cells are not well understood. To delineate epigenetic changes associated with EPO signaling, we compared histone H3 lysine 4 dimethylation (H3K4me2) in EPO treated and control fetal neural progenitor cells, identifying 1,150 differentially bound regions. These regions were highly enriched near protein coding genes and had significant overlap with H4Acetylation, a mark of active regulatory elements. Motif analyses and co-occupancy studies revealed a complex regulatory network underlying the differentially bound regions, including previously identified mediators of EPO signaling (STAT5, STAT3), and novel factors such as REST, an epigenetic modifier central to neural differentiation and plasticity, and NRF1, a key regulator of antioxidant response and mitochondrial biogenesis. Global transcriptome analyses on neural tubes isolated from E9.0 EpoR-null and littermate control embryos validated our in vitro findings, further suggesting a role for REST and NRF1 downstream of EPO signaling. These data support a role for EPO in regulating the survival, proliferation, and differentiation of neural progenitor cells, and suggest a basis for its function in neural development and neuroprotection. The human sequencing data is not shared publicly due to privacy concerns, but is available from the investigators on request

ORGANISM(S): Mus musculus

PROVIDER: GSE99372 | GEO | 2017/11/06

SECONDARY ACCESSION(S): PRJNA388212

REPOSITORIES: GEO

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Project description:Alcohol exposure during the formation and closure of the neural tube, or neurulation (embryonic day [E] 8-10 in mice; ∼4th week of human pregnancy), perturbs development of midline brain structures and significantly disrupts gene expression in the rostroventral neural tube (RVNT). Previously, alcohol exposure during neurulation was found to alter gene pathways related to cell proliferation, p53 signaling, ribosome biogenesis, immune signaling, organogenesis, and cell migration 6 or 24 hours after administration. Our current study expands upon this work by investigating short-term gene expression changes in the RVNT following a single binge-like alcohol exposure during neurulation. Female C57BL/6J mice were administered a single dose of 2.9 g/kg alcohol or vehicle on E9.0 to target mid-neurulation. The RVNTs of stage-matched embryos were collected 2 or 4 hours after exposure and processed for RNA-seq. Functional profiling was performed with g:Profiler, as well as the CiliaCarta and DisGeNet databases. Two hours following E9.0 alcohol exposure, 650 genes in the RVNT were differentially expressed. Functional enrichment analysis revealed that pathways related to cellular metabolism, gene expression, cell cycle, organogenesis, and Hedgehog signaling were down-regulated and pathways related to cellular stress response, p53 signaling, and hypoxia were up-regulated by alcohol. Four hours after alcohol, 225 genes were differentially expressed. Biological processes related to metabolism, RNA binding, ribosome biogenesis, and methylation were down-regulated, while protein localization and binding, autophagy, and intracellular signaling pathways were up-regulated. Two hr after alcohol, the differentially expressed genes were associated with disease terms related to eye and craniofacial development and anoxia. These data provide further information regarding the biological functions targeted by alcohol exposure during neurulation in regions of the neural tube that give rise to alcohol-sensitive midline brain structures. Disruption of these gene pathways contributes to the craniofacial and brain malformations associated with prenatal alcohol exposure.

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Erythropoietin Signaling Regulates Key Epigenetic and Transcription Networks in Fetal Neural Progenitor Cells

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