Functional partitioning of transcriptional regulators by patterned charge blocks
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA867741 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20994501.fastq.gz | Fastqsanger.gz | |||
| SRR20994502.fastq.gz | Fastqsanger.gz | |||
| SRR20994503.fastq.gz | Fastqsanger.gz | |||
| SRR20994504.fastq.gz | Fastqsanger.gz | |||
| SRR20994505.fastq.gz | Fastqsanger.gz |
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Project description:Components of the transcriptional machinery are dynamically compartmentalized by weak multivalent interactions, yet we know little about how specificity or selectivity of partitioning is achieved. Here we show that condensates composed of the intrinsically disordered region (IDR) of MED1 (MED1_IDR) selectively partition positive regulators of transcription(SPT6, CTR9, IWS1) with RNA Pol II while excluding negative regulators of transcription (NELF and HP1a).This selective compartmentalization by MED1_IDR is sufficient to activate transcription and is required for gene activation during a cell state transition. Surprisingly, the IDRs of partitioned proteins are sufficient to recapitulate selective compartmentalization. We find that IDR-mediated selective partitioning requires multivalent blocks of positive and negative charge on MED1_IDR and IDRs of partitioned proteins. The charge patterns required for partitioning are also required for gene activation. These findings demonstrate that proteins can be functionally compartmentalized by specific multivalent interactions driven by the charge patterning within disordered regions.
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Project description:Components of transcriptional machinery are selectively partitioned into specific condensates, often mediated by protein disorder, yet we know little about how this specificity is achieved. Here, we show that condensates composed of the intrinsically disordered region (IDR) of MED1 selectively partition RNA polymerase II together with its positive allosteric regulators while excluding negative regulators. This selective compartmentalization is sufficient to activate transcription and is required for gene activation during a cell-state transition. The IDRs of partitioned proteins are necessary and sufficient for selective compartmentalization and require alternating blocks of charged amino acids. Disrupting this charge pattern prevents partitioning, whereas adding the pattern to proteins promotes partitioning with functional consequences for gene activation. IDRs with similar patterned charge blocks show similar partitioning and function. These findings demonstrate that disorder-mediated interactions can selectively compartmentalize specific functionally related proteins from a complex mixture of biomolecules, leading to regulation of a biochemical pathway.
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Project description:GFP-MED1-IDR forms condensates when added to a soluble nuclear extract. Centrifugation fractionates the extract into a pellet fraction containing the proteins partitioned into MED1-IDR condensates and supernatant fraction containing proteins excluded from the MED1-IDR condensates. Two independent supernatant (LUM1_854558, LUM1_854560) and pellet (LUM1_854559, LUM1_854561) fractions were collected and subject to proteomic analysis to identify protein enriched in MED1-IDR condensates.
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Project description:Thousands of noncoding somatic Single Nucleotide Variants (SNVs) of unknown
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reveals the enrichment of somatic SNVs in prostate tumors as opposed to adjacent
normal tissue cistromes of master transcription regulators, including AR, FOXA1 and
HOXB13. This parallels enrichment of prostate cancer genetic predispositions over
these transcription regulators’ tumor cistromes, exemplified at the 8q24 locus harboring
both risk-variants and somatic SNVs in cis-regulatory elements, upregulating MYC
expression and altering the binding of transcription regulators to DNA. However, Massively-Parallel Reporter Assays reveal that few SNVs can alter the transactivation
potential of individual CREs. Instead, SNVs accumulate, similarly to inherited riskvariants,
in cistromes of master transcription regulators required for prostate cancer
development.
Difficulties in inferring the biological significance of noncoding mutations have limited
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role for noncoding mutations relied on detecting evidence for positive selection within
individual CREs, such as reported for the TERT gene promoter. By considering the
enrichment of noncoding mutations in cistromes as opposed to individual CREs, we
reveal their specificity towards master transcription regulators that promote prostate
cancer development, a feature shared with inherited risk-variants. Overall, our work
provides a blueprint for the functional interpretation of noncoding mutations in genomic
tests relying on defining cis-regulatory units according to cistrome-partitioning to
identify cancer driver transcription regulators.
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