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• Dufour, Damien; Zhao, Xu; Chaleil, Florian; Nothnagel, Patrizia Maria Christiane; Bjørås, Magnar & Lefrançois-Martinez, Anne-Marie [Show all 8 contributors for this article] (2025). Pharmacological inhibition of SUMOylation with TAK-981 mimics genetic HypoSUMOylation in murine perigonadal white adipose tissue. Adipocyte. ISSN 2162-3945. 14(1). doi: 10.1080/21623945.2025.2474107. Full text in Research Archive Show summary

  Post-translational modification by the small ubiquitin-like modifier (SUMO) is essential for cellular differentiation and homeostasis. Here, we investigate the role of SUMOylation in adipose tissue development using TAK-981, a pharmacological inhibitor of SUMOylation. Administration of TAK-981 to mice resulted in significant defect in weight gain and adipocyte atrophy in perigonadal white adipose tissue (gWAT) depots. Gene expression analyses revealed a marked downregulation of adipogenic genes, including Pparg, Cebpa, and Fasn. Our data thus indicate that TAK-981 treatment impaired adipogenesis in gWAT, consistent with prior findings that SUMOylation supports transcriptional regulation of adipogenesis and lipid metabolism. We also found significant infiltration of immune cells and efferocytosis in gWAT. Our results thus indicate that SUMOylation inhibition using a small molecule phenocopies genetic hypoSUMOylation models, highlighting its critical role in maintaining adipocyte functionality and immune environment. These findings provide evidence that SUMOylation is essential for fat accumulation in vivo. Furthermore, given that TAK-981 is currently under clinical evaluation for the treatment of solid tumors, our results underscore the importance of considering the potential unintended effects of SUMOylation inhibition on adipose tissue in patients.

• Bjune, Jan-Inge; Laber, Samantha; Dyer, Laurence; Nothnagel, Patrizia Maria Christiane; Yamada, Shuntaro & Zhao, Xu [Show all 15 contributors for this article] (2025). IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells. Nature Communications. 16. doi: 10.1038/s41467-025-62361-1. Full text in Research Archive Show summary

  IRX3 is linked to predisposition to obesity through the FTO locus and is upregulated during early adipogenesis in risk-allele carriers, shifting adipocyte fate toward fat storage. However, how this elevated IRX3 expression influences later developmental stages remains unclear. Here we show that IRX3 regulates adipocyte fate by modulating epigenetic reprogramming. ChIP-sequencing in preadipocytes identifies over 300 IRX3 binding sites, predominantly at promoters of genes involved in SUMOylation and chromatin remodeling. IRX3 knockout alters expression of SUMO pathway genes, increases global SUMOylation, and inhibits PPARγ activity and adipogenesis. Pharmacological SUMOylation inhibition rescues these effects. IRX3 KO also reduces SUMO occupancy at Wnt-related genes, enhancing Wnt signaling and promoting osteogenic fate in 3D cultures. This fate switch is partially reversible by SUMOylation inhibition. We identify IRX3 as a key transcriptional regulator of epigenetic programs, acting upstream of SUMOylation to maintain mesenchymal identity and support adipogenesis while suppressing osteogenesis in mouse embryonic fibroblasts.

• Alonso, Lucia Ramos; Holland, Petter; Gras, Stéphanie Le; Zhao, Xu; Jost, Bernard & Bjørås, Magnar [Show all 9 contributors for this article] (2023). Mitotic chromosome condensation resets chromatin to safeguard transcriptional homeostasis during interphase. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 120(4). doi: 10.1073/pnas.2210593120. Full text in Research Archive Show summary

  Mitotic entry correlates with the condensation of the chromosomes, changes in histone modifications, exclusion of transcription factors from DNA, and the broad downregulation of transcription. However, whether mitotic condensation influences transcription in the subsequent interphase is unknown. Here, we show that preventing one chromosome to condense during mitosis causes it to fail resetting of transcription. Rather, in the following interphase, the affected chromosome contains unusually high levels of the transcription machinery, resulting in abnormally high expression levels of genes in cis, including various transcription factors. This subsequently causes the activation of inducible transcriptional programs in trans, such as the GAL genes, even in the absence of the relevant stimuli. Thus, mitotic chromosome condensation exerts stringent control on interphase gene expression to ensure the maintenance of basic cellular functions and cell identity across cell divisions. Together, our study identifies the maintenance of transcriptional homeostasis during interphase as an unexpected function of mitosis and mitotic chromosome condensation.

• Gao, Pan; Liu, Shun; Zhao, Xu & Yu, Hao (2022). Bi-objective Optimization of Ship Dam-passing Appointment Scheduling Considering Green Navigation. Jiaotong Yunshu Xitong Gongcheng Yu Xinxi. ISSN 1009-6744. 22(5). doi: 10.16097/j.cnki.1009-6744.2022.05.030. Full text in Research Archive
• Zhao, Xu; Hendriks, Ivo A; Gras, Stephanie Le; Ye, Tao; Alonso, Lucia Ramos & P, Aurélie Nguéa [Show all 13 contributors for this article] (2022). Waves of sumoylation support transcription dynamics during adipocyte differentiation. Nucleic Acids Research (NAR). ISSN 0305-1048. 50(3), p. 1351–1369. doi: 10.1093/nar/gkac027. Full text in Research Archive Show summary

  Abstract Tight control of gene expression networks required for adipose tissue formation and plasticity is essential for adaptation to energy needs and environmental cues. However, the mechanisms that orchestrate the global and dramatic transcriptional changes leading to adipocyte differentiation remain to be fully unraveled. We investigated the regulation of nascent transcription by the sumoylation pathway during adipocyte differentiation using SLAMseq and ChIPseq. We discovered that the sumoylation pathway has a dual function in differentiation; it supports the initial downregulation of pre-adipocyte-specific genes, while it promotes the establishment of the mature adipocyte transcriptional program. By characterizing endogenous sumoylome dynamics in differentiating adipocytes by mass spectrometry, we found that sumoylation of specific transcription factors like PPARγ/RXR and their co-factors are associated with the transcription of adipogenic genes. Finally, using RXR as a model, we found that sumoylation may regulate adipogenic transcription by supporting the chromatin occurrence of transcription factors. Our data demonstrate that the sumoylation pathway supports the rewiring of transcriptional networks required for formation of functional adipocytes. This study also provides the scientists in the field of cellular differentiation and development with an in-depth resource of the dynamics of the SUMO-chromatin landscape, SUMO-regulated transcription and endogenous sumoylation sites during adipocyte differentiation.

• Li, Miaomiao; Zhao, Xu; Wang, Wei; Shi, Hailing; Pan, Qingfei & Lu, Zhike [Show all 11 contributors for this article] (2018). Ythdf2-mediated m6A mRNA clearance modulates neural development in mice. Genome Biology. ISSN 1465-6906. 19(1). doi: 10.1186/s13059-018-1436-y. Full text in Research Archive Show summary

  Background N 6 -methyladenosine (m6A) modification in mRNAs was recently shown to be dynamically regulated, indicating a pivotal role in multiple developmental processes. Most recently, it was shown that the Mettl3-Mettl14 writer complex of this mark is required for the temporal control of cortical neurogenesis. The m6A reader protein Ythdf2 promotes mRNA degradation by recognizing m6A and recruiting the mRNA decay machinery. Results We show that the conditional depletion of the m6A reader protein Ythdf2 in mice causes lethality at late embryonic developmental stages, with embryos characterized by compromised neural development. We demonstrate that neural stem/progenitor cell (NSPC) self-renewal and spatiotemporal generation of neurons and other cell types are severely impacted by the loss of Ythdf2 in embryonic neocortex. Combining in vivo and in vitro assays, we show that the proliferation and differentiation capabilities of NSPCs decrease significantly in Ythdf2 −/− embryos. The Ythdf2 −/− neurons are unable to produce normally functioning neurites, leading to failure in recovery upon reactive oxygen species stimulation. Consistently, expression of genes enriched in neural development pathways is significantly disturbed. Detailed analysis of the m6A-methylomes of Ythdf2 −/− NSPCs identifies that the JAK-STAT cascade inhibitory genes contribute to neuroprotection and neurite outgrowths show increased expression and m6A enrichment. In agreement with the function of Ythdf2, delayed degradation of neuron differentiation-related m6A-containing mRNAs is seen in Ythdf2 −/− NSPCs. Conclusions We show that the m6A reader protein Ythdf2 modulates neural development by promoting m6A-dependent degradation of neural development-related mRNA targets.

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• Abdulkadir, Mohammed A.; Alay, Özgü; Dreibholz, Thomas; Elmokashfi, Ahmed; Li, Xi & Lopez, Diego [Show all 13 contributors for this article] (2021). AI and ML – Enablers for Beyond 5G Networks. 5G PPP Technology Board. doi: 10.5281/zenodo.429989. Full text in Research Archive Show summary

  This white paper on AI and ML as enablers of beyond 5G (B5G) networks is based on contributions from almost 20 5G PPP projects, coordinated through the 5G PPP Technology Board, that research, implement and validate 5G and B5G network systems. The paper introduces the main relevant mechanisms in Artificial Intelligence (AI) and Machine Learning (ML), currently investigated and exploited for enhancing 5G and B5G networks.

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