MED26-mediated phase separation regulates erythropoiesis by tuning transcription pausing
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ABSTRACT:
PROVIDER: PRJNA875137 | ENA |
REPOSITORIES: ENA
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Project description:The Mediator complex plays a pivotal role in various aspects of transcription and development. However, it remains unclear whether individual Mediator subunits play differential roles during the progression of the developmental process. In this study, we found that the protein level of MED26, a subunit in the core Mediator complex, remained relatively abundant in terminal erythropoiesis, while that of most Mediator subunits drastically diminished. MED26 exhibits pronounced phase separation capability, which is essential for erythroid differentiation of primary human erythroblasts. Interestingly, we found that ~60% of chromatin sites with MED26 or MED1 occupancy did not co-localize. Moreover, MED26-enriched loci were associated with RNA polymerase II pausing, and MED26 preferentially interacted with transcription pausing factors, including PAF1, via its TFIIS domain. During erythropoiesis, both the relative abundance of MED26 and the Pausing Index (PI) increased. Erythroid differentiation was promoted by small molecule-induced PI elevation or overexpression of MED26—full-length or the IDR alone—indicating that MED26-associated pausing is necessary for erythropoiesis. In conclusion, this study revealed that MED26 tunes transcription pausing to facilitate erythroid development via a phase separation mechanism.
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Project description:Chromosome translocation is known to generate oncogenes such as SS18-SSX1, but the underlying mechanism remains unknown. Here we show that enhanced phase separation acquired by translocation mediates oncogenic transformation. SSX fusion dramatically enhances the phase separation property of SS18 protein through H2AK119ub. Super condensates generated by SS18-SSX recruit acetyltransferases CBP/P300 as wild type SS18, but exclude HDACs such that H3K27ac accumulates abnormally at loci from those normally occupied by SS18, resulting aberrant silencing and activation of target genes. Consistently, we show that inhibition of H3K27ac can attenuate the tumorigenicity of the fusion oncoprotein (we do not have the data in your figures?). These results provide the first case for phase separation as a transforming event to generate oncogene and super phase separation can be targeted for cancer therapy.
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Project description:Chromosome translocation is known to generate oncogenes such as SS18-SSX1, but the underlying mechanism remains unknown. Here we show that enhanced phase separation acquired by translocation mediates oncogenic transformation. SSX fusion dramatically enhances the phase separation property of SS18 protein through H2AK119ub. Super condensates generated by SS18-SSX recruit acetyltransferases CBP/P300 as wild type SS18, but exclude HDACs such that H3K27ac accumulates abnormally at loci from those normally occupied by SS18, resulting aberrant silencing and activation of target genes. Consistently, we show that inhibition of H3K27ac can attenuate the tumorigenicity of the fusion oncoprotein. These results provide the first case for phase separation as a transforming event to generate oncogene and super phase separation can be targeted for cancer therapy.
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Project description:Chromosome translocation is known to generate oncogenes such as SS18-SSX1, but the underlying mechanism remains unknown. Here we show that enhanced phase separation acquired by translocation mediates oncogenic transformation. SSX fusion dramatically enhances the phase separation property of SS18 protein through H2AK119ub. Super condensates generated by SS18-SSX recruit acetyltransferases CBP/P300 as wild type SS18, but exclude HDACs such that H3K27ac accumulates abnormally at loci from those normally occupied by SS18, resulting aberrant silencing and activation of target genes. Consistently, we show that inhibition of H3K27ac can attenuate the tumorigenicity of the fusion oncoprotein. These results provide the first case for phase separation as a transforming event to generate oncogene and super phase separation can be targeted for cancer therapy.
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