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Phosphorylation of 53BP1 by ATM enforce neurodevelopmental programs in cortical organoids

ABSTRACT: 53BP1 is a well-established DNA damage repair factor that has recently been shown to regulate gene expression and critically influence tumor suppression and neural development. For gene regulation, how 53BP1 is regulated remains unclear. Here, we showed that 53BP1-serine 25 phosphorylation by ATM is required for neural progenitor cell proliferation and neuronal differentiation in cortical organoids. 53BP1-serine 25 phosphorylation dynamics controls 53BP1 target genes for neuronal differentiation and function, cellular response to stress, and apoptosis. Beyond 53BP1, ATM is required for phosphorylation of factors in neuronal differentiation, cytoskeleton, p53 regulation, and ATM, BNDF, and WNT signaling pathways for cortical organoid differentiation. Overall, our data suggest that 53BP1 and ATM control key genetic programs required for human cortical development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231321 | GEO | 2024/08/11

REPOSITORIES: GEO

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Project description:Purpose: CREB (cAMP response element binding protein) is a transcription factor that is critical for learning and memory. The activity of CREB is mediated through its post-translational modifications (PTMs); specifically, phosphorylation at serine 133 and glycosylation at serine 40. In this study, we used RNA-Seq and weighted gene network coexpression analysis (WGCNA) to determine the CREB-mediated transcriptional programmes that are regulated by phosphorylation at serine 133 and glycosylation at serine 40 through the use of various PTM-deficient CREB mutants. Methods: The mRNA profiles of E16.5 Creb1-/- mouse cortical neurons expressing GFP, WT CREB, S40A-CREB, S133A-CREB, and S40A-S133A-CREB were generated by deep sequencing, in triplicate, using Illumina HiSeq 2500. The sequence reads that passed quality filters were analyzed using Bowtie, aligned using TopHat, and quantified using Cufflinks in Galaxy. Results: Through differential expression analysis with glycosylation-deficient (S40A) and phosphorylation-deficient (S133A) CREB mutants, we show that CREB O-GlcNAcylation is important for neuronal activity and excitability, while phosphorylation at serine 133 regulates the expression of genes involved in neuronal differentiation. Furthermore, many of the S40A and S133A differentially-expressed genes were directly bound by (1) CREB and its co-activators, CREB-binding protein and p300, (2) activating histone modifications, (3) OGT and O-GlcNAc, and (4) Tet1, an critical regulator of neuronal activity and differentiation. Finally, we observed a positive correlation between S40A and activity- and excitotoxicity-related gene networks and a negative correlation between S133A and neuronal differentiation and amino and fatty acid metabolism-related gene networks. This study demonstrates that CREB O-GlcNAcylation at serine 40 and phosphorylation mediate mutually exclusive gene networks. Together, O-GlcNAc and phosphorylation impart a TF code, which CREB must integrate and decode to modulate neuronal activity, differentiation, and metabolism.

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Phosphorylation of 53BP1 by ATM enforce neurodevelopmental programs in cortical organoids

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