Transcriptomic atlas of adult primate brain progenitor cells

The adult brain retains capability to regenerate via stem cells known as neural stem/progenitor cells. The research onto the molecular signals which regulate neuronal production by stem cells is an intensely studied topic. However, currently it largely remains unknown how these mechanisms operate in the primate brain.

Together with groups from Germany, Japan and China, MU-Varna researchers from the TRANSTEM team have published the first transcriptomic analysis of gene expression in the neural stem niche of the adult brain of macaque monkeys. In order to uncover genes which could potentially activate the process of neurogenesis in the main stem cell zone of the adult brain, known as the subventricular zone, we compared the changes in the gene expression before and after ischemic insult, known as a strong activator of neurogenesis. Our results uncovered 500 genes up-regulated after ischemia in the subventricular zone. Some of these genes were already known as stem cell-related from data in mice, while others seemed to be specific for the primate brain. We also employed an in situ gene expression analysis on histological sections of 150 genes, the data available in a public database: www.monkey-niche.org. The results are published in Frontiers in Cell and Developmental Biology.

Fulltext citation: Chongtham MC, Wang H, Thaller C, Hsiao NH, Vachkov IH, Pavlov SP, Williamson LH, Yamashima T, Stoykova A, Yan J, Eichele G, Tonchev AB. Transcriptome Response and Spatial Pattern of Gene Expression in the Primate Subventricular Zone Neurogenic Niche After Cerebral Ischemia. Front Cell Dev Biol. 2020 Dec 3;8:584314. doi: https://doi.org/10.3389/fcell.2020.584314

A new mouse model for hyper-sociality and regeneration of the hippocampus

Gene expression and epigenetic processes in several brain regions regulate physiological processes such as cognitive functions and social behavior. MacroH2A1.1 is a ubiquitous variant of histone H2A that regulates cell stemness and differentiation in various organs. Whether macroH2A1.1 has a modulatory role in emotional behavior is unknown. 

Together with groups from Italy (Rome, Catania) and Czech Republic (Brno), researchers from the TRANSTEM team employed macroH2A1.1 knock-out (−/−) mice to perform a comprehensive battery of behavioral tests, and an assessment of hippocampal synaptic plasticity (long- term potentiation) accompanied by whole hippocampus RNA sequencing. MacroH2A1.1−/− mice exhibit a stunning enhancement both of sociability and of active stress- coping behavior, reflected by the increased social behavior in social activity tests and higher mobility time in the forced swim test, respectively. They also display an increased hippocampal synaptic plasticity, accompanied by significant neurotransmission transcriptional networks changes. These results suggest that systemic depletion of histone macroH2A1.1 supports an epigenetic control necessary for hippocampal function and social behavior.

This mouse model can be used for studies on hypersociability and on autism.

Fulltext citation: Chiodi,V, Domenici MR, Biagini T, De Simone R, Tartaglione AM, Di Rosa, M, Lo Re O, Mazza T, Micale V, Vinciguerra M. Systemic depletion of histone macroH2A1.1 boosts hippocampal synaptic plasticity and social behaviour in mice. FASEB Journal 2021; 35:e21793. https://doi.org/10.1096/fj.202100569R

Increasing the efficiency of production of reprogrammed iPSCs

DDR efficiency could increase the yield of induced pluripotent stem cells (iPSC) upon reprogramming from somatic cells. The epigenetic mechanisms governing DDR during iPSC reprogramming are not completely understood. The goal was to evaluate the splicing isoforms of histone variant macroH2A1, macroH2A1.1, and macroH2A1.2, as potential regulators of DDR during iPSC reprogramming.

Together with groups from Italy (Rome), United Kingdom (Liverpool), Estonia (Tallinn) and Czech Republic (Brno), researchers from the TRANSTEM team used GFP-Trap one-step isolation of mtagGFP-macroH2A1.1 or mtagGFP-macroH2A1.2 fusion proteins from overexpressing human cell lines, followed by liquid chromatography-tandem mass spectrometry analysis, to uncover macroH2A1.1 exclusive interaction with Poly-ADP Ribose Polymerase 1 (PARP1) and X-ray cross-complementing protein 1 (XRCC1). MacroH2A1.1 overexpression in U2OS-GFP reporter cells enhanced specifically nonhomologous end joining (NHEJ) repair pathway, while macroH2A1.1 knock-out (KO) mice showed an impaired DDR capacity. The exclusive interaction of macroH2A1.1, but not macroH2A1.2, with PARP1/XRCC1, was confirmed in human umbilical vein endothelial cells (HUVEC) undergoing reprogramming into iPSC through episomal vectors. In HUVEC, macroH2A1.1 overexpression activated transcriptional programs that enhanced DDR and reprogramming. Consistently, macroH2A1.1 but not macroH2A1.2 overexpression improved iPSC reprogramming.

MacroH2A1 splicing isoform macroH2A1.1 was proposed as a promising epigenetic target to improve iPSC genome stability and therapeutic potential.

Fulltext citation: Giallongo S, Reháková D, Biagini T, Lo Re O, Raina P, Lochmanová G, Zdráhal Z, Resnick I, Pata P, Pata I, Mistrík M, de Magalhães JP, Mazza T, Koutná I, Vinciguerra M. Histone Variant macroH2A1.1 Enhances Nonhomologous End Joining-dependent DNA Double-strand-break Repair and Reprogramming Efficiency of Human iPSCs. Stem Cells, Volume 40, Issue 1, January 2022, Pages 35–48, https://doi.org/10.1093/stmcls/sxab004