SUMOylation of Bonus, the Drosophila homolog of Transcription Intermediary Factor 1, safeguards germline identity by recruiting repressive chromatin complexes to silence tissue-specific genes
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1.
California Institute of Technology
Abstract
The conserved family of Transcription Intermediary Factors (TIF1) proteins consists of key transcriptional regulators that control transcription of target genes by modulating chromatin state. Unlike mammals that have four TIF1 members, Drosophila only encodes one member of the family, Bonus. Bonus has been implicated in embryonic development and organogenesis and shown to regulate several signaling pathways, however, its targets and mechanism of action remained poorly understood. We found that knockdown of Bonus in early oogenesis results in severe defects in ovarian development and in ectopic expression of genes that are normally repressed in the germline, demonstrating its essential function in the ovary. Recruitment of Bonus to chromatin leads to silencing associated with accumulation of the repressive H3K9me3 mark. We show that Bonus associates with the histone methyltransferase SetDB1 and the chromatin remodeler NuRD and depletion of either component releases Bonus-induced repression. We further established that Bonus is SUMOylated at a single site at its N-terminus that is conserved among insects and this modification is indispensable for Bonus's repressive activity. SUMOylation influences Bonus's subnuclear localization, its association with chromatin and interaction with SetDB1. Finally, we showed that Bonus SUMOylation is mediated by the SUMO E3-ligase Su(var)2–10, revealing that although SUMOylation of TIF1 proteins is conserved between insects and mammals, both the mechanism and specific site of modification is different in the two taxa. Together, our work identified Bonus as a regulator of tissue-specific gene expression and revealed the importance of SUMOylation as a regulator of complex formation in the context of transcriptional repression.
Copyright and License
© 2023, Godneeva et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Acknowledgement
We thank members of the Aravin and Fejes Toth labs for discussion. We thank Peiwei Chen for suggesting some of the experiments. We appreciate the help of Anastasiya Grebin with the experiments. We are grateful to Julius Brennecke, Gregory Hannon, Albert Courey, the Bloomington Stock Center, and the Vienna Drosophila Resource Center for providing fly stocks, Hugo Bellen for providing antibodies. We thank Igor Antoshechkin (Millard and Muriel Jacobs Genetics and Genomics Laboratory, Caltech) for the help with sequencing, Giada Spigolon (Biological Imaging Facility, Caltech) for the help with microscopy, and Grace Shin for the help with HCR experiments. This work was supported by grants from the National Institutes of Health (R01 GM097363 to A.A.A. and R01 GM110217 to K.F.T. and R00 HD099316 to M.N.) and by the HHMI Faculty Scholar Award to A.A.A.
Funding
The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.
National Institutes of Health R01 GM097363 to Alexei Aravin.
National Institutes of Health R01 GM110217 to Katalin Fejes-Toth.
Howard Hughes Medical Institute Faculty Scholar Award to Alexei Aravin.
National Institutes of Health R00 HD099316 to Maria Ninova.
Data Availability
The sequencing datasets have been deposited to the NCBI GEO archive under accession code GSE241375.
The following dataset was generated:
Godneeva B. 2023. SUMOylation of Bonus, the Drosophila homolog of Transcription Intermediary Factor 1, safeguards germline identity by recruiting repressive chromatin complexes to silence tissue-specific genes. NCBI Gene Expression Omnibus. GSE241375
Contributions
Baira Godneeva, Conceptualization, Software, Formal analysis, Investigation, Visualization, Methodology, Writing – original draft; Maria Ninova, Conceptualization, Software, Formal analysis, Methodology, Writing – review and editing; Katalin Fejes-Toth, Alexei Aravin, Conceptualization, Formal analysis, Funding acquisition, Methodology, Writing – review and editing
Conflict of Interest
No competing interests declared.
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Additional details
- PMCID
- PMC10672805
- R01 GM097363
- National Institutes of Health
- R01 GM110217
- National Institutes of Health
- Howard Hughes Medical Institute
- R00 HD099316
- National Institutes of Health
- Caltech groups
- Tianqiao and Chrissy Chen Institute for Neuroscience, Division of Biology and Biological Engineering