MeCP2 represses the activity of topoisomerase IIβ in long neuronal genes

• Published in: Cell reports (Cambridge) Vol. 42; no. 12; p. 113538
• Main Authors: Nettles, Sabin A., Ikeuchi, Yoshiho, Lefton, Katheryn B., Abbasi, Ladan, Erickson, Alyssa, Agwu, Chibueze, Papouin, Thomas, Bonni, Azad, Gabel, Harrison W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26-12-2023; Elsevier
• Subjects: Animals; brain; CP: Neuroscience; enhancer; gene regulation; long genes; MeCP2; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice; neurodevelopmental disorders; Neurons - metabolism; Rett syndrome; Rett Syndrome - genetics; TOP2β; transcription; TOP2β; MeCP2; enhancer; transcription; gene regulation; CP: Neuroscience; Rett syndrome; long genes; brain; neurodevelopmental disorders
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113538

A unique signature of neurons is the high expression of the longest genes in the genome. These genes have essential neuronal functions, and disruption of their expression has been implicated in neurological disorders. DNA topoisomerases resolve DNA topological constraints and facilitate neuronal long gene expression. Conversely, the Rett syndrome protein, methyl-CpG-binding protein 2 (MeCP2), can transcriptionally repress long genes. How these factors regulate long genes is not well understood, and whether they interact is not known. Here, we identify and map a functional interaction between MeCP2 and topoisomerase IIβ (TOP2β) in mouse neurons. We profile neuronal TOP2β activity genome wide, detecting enrichment at regulatory regions and gene bodies of long genes, including MeCP2-regulated genes. We show that loss and overexpression of MeCP2 alter TOP2β activity at MeCP2-regulated genes. These findings uncover a mechanism of TOP2β inhibition by MeCP2 in neurons and implicate TOP2β dysregulation in disorders caused by MeCP2 disruption.
[Display omitted]
•TOP2β is an MeCP2-interacting protein in neurons•TOP2β activity is enriched at promoters and enhancers of long neuronal genes•MeCP2 represses TOP2β activity at regulatory regions within MeCP2-regulated genes•Loss of MeCP2 leads to hyperactivation of TOP2β in long genes regulated by MeCP2
Nettles et al. establish TOP2β as an MeCP2-interacting protein and demonstrate that MeCP2 negatively regulates TOP2β activity at MeCP2-repressed long genes in neurons. Their results implicate aberrant TOP2β activity in long neuronal genes in the pathology of Rett syndrome.