DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes
Open accessAbstract
Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.
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A general antagonistic activity of the NCOR1/HDAC3 complex in regulating H3K27ac turnover at genomic loci under CREBBP or EP300 supervision was confirmed.
“A general antagonistic activity of the NCOR1/HDAC3 complex in regulating H3K27ac turnover at genomic loci under the supervision of CREBBP or EP300 was confirmed by additional studies (Basu et al., 2020).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Basu et al., 2020
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- Authors
- Basu, S., Barad, M., Yadav, D., Nandy, A., Mukherjee, B., Sarkar, J., Chakrabarti, P., Mukhopadhyay, S., & Biswas, D.
- Affiliations
- Indian Institute of Chemical Biology (IN)
- Institute of Post Graduate Medical Education and Research (IN)
- Corresponding author
- Biswas, Debabrata
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-03-09
- Volume
- 117
- Issue
- 12
- Pages
- 6509-6520
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7104407
- OpenAlex
- W3009560374
- Cited by
- 22
- References
- 35
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 5 · 2022: 7 · 2021: 5 · 2020: 1
- FWCI
- 1.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wellcome-Trust DBT India Alliance (IA/I/14/1/501287)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- DBC1, P300, HDAC3, SIAH1, protein stability, transcription elongation, RNA polymerase II, histone acetylation, histone deacetylation, polyubiquitination, E3 ubiquitin ligase, super elongation complex, glucose metabolism, type 2 diabetes, peripheral blood mononuclear cells
- MeSH terms
- Seven in Absentia Proteins, Histone Deacetylase 3, Acetylation, Animals, Binding Sites, Cell Line, Diabetes Mellitus, Type 2, Gene Expression Regulation, Glucose, Histone Deacetylases, Humans, Leukocytes, Mononuclear, Mutation, Nuclear Proteins, Protein Binding, Transcription, Genetic, Transcriptional Elongation Factors, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, E1A-Associated p300 Protein, Ubiquitination, Protein Stability, Gene Knockdown Techniques
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