Autoinhibition of ASXL1 Condensation via Opposing-Charge Blocks in Its Disordered Region
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE297436 | GEO | 2026/04/09
REPOSITORIES: GEO
Similar Datasets
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.
2023-01-03 | GSE210875 | GEO
Project description:Nuclear speckles (NSs) are viscoelastic network fluids formed via phase separation coupled to percolation (PSCP). Intermolecular cross-links of SRRM2, a key scaffold of NSs lead to the emergence of system-spanning networks, although the physiochemical grammar governing SRRM2 PSCP remains poorly decoded. Here, we demonstrate that SRRM2 is extensively phosphorylated within the intrinsically disordered domain (IDR) that are prominently positively charged. Rather than attaching phosphate groups to specific sites, the purpose of phosphorylation is to create alternating charge blocks. Employing a suite of biophysical approach, we show that in contrast to the leading theories that charge blocks lower condensation threshold of biopolymers, this specific charge pattern does not markedly alter the percolation threshold of SRRM2 in cells. Instead, SRRM2 charge blocks intensify intra-network molecular interactions to modulate the material properties of mesoscopic SRRM2 condensates. We further identify casein kinase 2 (CK2) as the upstream enzyme to catalyze SRRM2 phosphorylation. Phosphorylation of SRRM2 IDR by CK2 facilitates NS relaxation under physiological condition, but can be employed to safeguard genome stability in times of DNA damage. Our findings reveal important regulatory mechanisms of charge blocks and functionality in modulating the material properties of biomolecular condensates in cells. We interpretate our observation in the theoretical framework of stickers-and-spacers model. In addition to the chemistry- or sequence-specific associative interaction, spacers (e.g. SRRM2 IDR) can also engage in charge pattern-specific molecular interactions, which are spatiotemporally regulated, to dictate the biophysical properties of percolated macromolecular assemblies.
2025-03-10 | GSE286350 | GEO
Project description:The transcription factor SREBP2, plays a specific and non-redundant role in cholesterol metabolism, autophagy of lipid droplets and apoptosis regulation. Under cholesterol-depletion condition, nuclear SREBP2 (nSREBP2) is released after proteolytic cleavage, enters nucleus and activates cholesterogenic genes expression. Here, we report that the nSREBP2 forms discrete nuclear condensates through its N-terminal intrinsically disordered region (IDR) and works together with transcription coactivators BRD4 and p300, partly on super-enhancers, for the transcriptional activation of SREBP2 target genes. The substitution of a critical and conserved phenylalanine (F) to alanine (A) within the IDR abolished the formation of nSREBP2 condensates. Conversely, the condensate formation and efficient transcription activation were rescued by fusion with a phase separation driving FUS-IDR. Knock-in of the F to A substitution in mice compromised the feeding-induced nSREBP2 activity and lowered the cholesterol levels. Furthermore, a SNP of SREBF2 in humans leading to single amino acid change, P183S, showed less nuclear condensate formation and lower transcriptional activity, underscoring the physiological relevance of nSREBP2 condensates. Together, this study reveals that nuclear condensates driven by the N terminal IDR of nSREBP2 facilitate the efficient activation of lipogenic genes and play an important role in cholesterol homeostasis.
2025-03-16 | GSE267019 | GEO
Project description:The transcription factor SREBP2, plays a specific and non-redundant role in cholesterol metabolism, autophagy of lipid droplets and apoptosis regulation. Under cholesterol-depletion condition, nuclear SREBP2 (nSREBP2) is released after proteolytic cleavage, enters nucleus and activates cholesterogenic genes expression. Here, we report that the nSREBP2 forms discrete nuclear condensates through its N-terminal intrinsically disordered region (IDR) and works together with transcription coactivators BRD4 and p300, partly on super-enhancers, for the transcriptional activation of SREBP2 target genes. The substitution of a critical and conserved phenylalanine (F) to alanine (A) within the IDR abolished the formation of nSREBP2 condensates. Conversely, the condensate formation and efficient transcription activation were rescued by fusion with a phase separation driving FUS-IDR. Knock-in of the F to A substitution in mice compromised the feeding-induced nSREBP2 activity and lowered the cholesterol levels. Furthermore, a SNP of SREBF2 in humans leading to single amino acid change, P183S, showed less nuclear condensate formation and lower transcriptional activity, underscoring the physiological relevance of nSREBP2 condensates. Together, this study reveals that nuclear condensates driven by the N terminal IDR of nSREBP2 facilitate the efficient activation of lipogenic genes and play an important role in cholesterol homeostasis.
2025-03-16 | GSE267018 | GEO
Project description:The transcription factor SREBP2, plays a specific and non-redundant role in cholesterol metabolism, autophagy of lipid droplets and apoptosis regulation. Under cholesterol-depletion condition, nuclear SREBP2 (nSREBP2) is released after proteolytic cleavage, enters nucleus and activates cholesterogenic genes expression. Here, we report that the nSREBP2 forms discrete nuclear condensates through its N-terminal intrinsically disordered region (IDR) and works together with transcription coactivators BRD4 and p300, partly on super-enhancers, for the transcriptional activation of SREBP2 target genes. The substitution of a critical and conserved phenylalanine (F) to alanine (A) within the IDR abolished the formation of nSREBP2 condensates. Conversely, the condensate formation and efficient transcription activation were rescued by fusion with a phase separation driving FUS-IDR. Knock-in of the F to A substitution in mice compromised the feeding-induced nSREBP2 activity and lowered the cholesterol levels. Furthermore, a SNP of SREBF2 in humans leading to single amino acid change, P183S, showed less nuclear condensate formation and lower transcriptional activity, underscoring the physiological relevance of nSREBP2 condensates. Together, this study reveals that nuclear condensates driven by the N terminal IDR of nSREBP2 facilitate the efficient activation of lipogenic genes and play an important role in cholesterol homeostasis.
2025-03-16 | GSE282800 | GEO
Project description:Bacterial adaptation to stress involves changes in transcription and mRNA degradation rates. In Escherichia coli, the Nudix hydrolase RppH initiates mRNA degradation by removing pyrophosphate from mRNA 5’-ends, converting 5’-triphosphates to 5’-monophosphates. We aimed to identify the RppH homolog in the globally important pathogen Mycobacterium tuberculosis (Mtb). We deleted each non-essential Nudix gene from Mtb to determine their impacts on mRNA 5’-phosphorylation. Deletion of mutT4 (Rv3908) increased the relative abundance of 5’-triphosphates on myriad mRNAs across the transcriptome. Purified MutT4 converted mRNA 5’-triphosphates into monophosphates, and stimulated degradation by RNase E and RNase J. MutT4 has intrinsically disordered regions (IDRs), a common domain for biomolecular condensate formation. Microscopy showed that MutT4 forms condensates that dissociate upon addition of rifampicin, and that the N-terminal IDR is sufficient for condensate formation. These MutT4 condensates localize with RNase E and RNase J. Deletion of mutT4 in Mtb leads to a higher outer membrane permeability and resistance to oxidative stress. We conclude that MutT4 is the RppH of Mtb, assembling in condensates that may act as degradation hubs. Our data indicate that MutT4 is unlikely to participate in DNA repair or nucleotide pool cleansing, and as such would more accurately be called RppH.
2025-03-26 | GSE292713 | GEO
Project description:Intrinsically disordered regions (IDRs) have emerged as crucial regulators of protein function, allowing proteins to sense and respond to their environment. Creb binding protein (CBP) and EP300 (p300) are transcription coactivators that regulate gene expression in multicellular organisms, following their recruitment to cis-regulatory elements. CBP and p300 contain large IDRs, however little is known about how these different IDRs work together to regulate CBP function. Here, we show that CBP-IDRs cooperate to control different aspects of CBP behaviour in the nucleus, by regulating the properties of fluid-like condensates formed by endogenous CBP. We show how IDRs with different sequence properties make unique contributions to CBP behaviour by establishing a balance between positive and negative regulation of CBP condensates. These conflicting interactions are functionally important, shaping CBPs response to factors such as lysine acetylation, that influence condensate formation. When disrupted, regulatory CBP-IDRs change how CBP interacts with chromatin, alter patterns of CBP-dependent histone acetylation and change gene expression. Together, our work highlights how IDRs with different sequences, spatially segregated in the same protein, can cooperate to shape protein function.
2026-02-23 | GSE299614 | GEO
Project description:Intrinsically disordered regions (IDRs) have emerged as crucial regulators of protein function, allowing proteins to sense and respond to their environment. Creb binding protein (CBP) and EP300 (p300) are transcription coactivators that regulate gene expression in multicellular organisms, following their recruitment to cis-regulatory elements. CBP and p300 contain large IDRs, however little is known about how these different IDRs work together to regulate CBP function. Here, we show that CBP-IDRs cooperate to control different aspects of CBP behaviour in the nucleus, by regulating the properties of fluid-like condensates formed by endogenous CBP. We show how IDRs with different sequence properties make unique contributions to CBP behaviour by establishing a balance between positive and negative regulation of CBP condensates. These conflicting interactions are functionally important, shaping CBPs response to factors such as lysine acetylation, that influence condensate formation. When disrupted, regulatory CBP-IDRs change how CBP interacts with chromatin, alter patterns of CBP-dependent histone acetylation and change gene expression. Together, our work highlights how IDRs with different sequences, spatially segregated in the same protein, can cooperate to shape protein function.
2026-02-23 | GSE299613 | GEO
Project description:Intrinsically disordered regions (IDRs) have emerged as crucial regulators of protein function, allowing proteins to sense and respond to their environment. Creb binding protein (CBP) and EP300 (p300) are transcription coactivators that regulate gene expression in multicellular organisms, following their recruitment to cis-regulatory elements. CBP and p300 contain large IDRs, however little is known about how these different IDRs work together to regulate CBP function. Here, we show that CBP-IDRs cooperate to control different aspects of CBP behaviour in the nucleus, by regulating the properties of fluid-like condensates formed by endogenous CBP. We show how IDRs with different sequence properties make unique contributions to CBP behaviour by establishing a balance between positive and negative regulation of CBP condensates. These conflicting interactions are functionally important, shaping CBPs response to factors such as lysine acetylation, that influence condensate formation. When disrupted, regulatory CBP-IDRs change how CBP interacts with chromatin, alter patterns of CBP-dependent histone acetylation and change gene expression. Together, our work highlights how IDRs with different sequences, spatially segregated in the same protein, can cooperate to shape protein function.
2026-02-23 | GSE268266 | GEO
Project description:TFIID is an essential eukaryotic transcription factor, which is required for RNA polymerase II promoter recognition and activation. As a multiprotein complex, TFIID contains several intrinsically disordered regions (IDRs), but the functions of these IDRs are unknown. Here, we show that a conserved IDR drives the TFIID subunit TAF2 to nuclear speckles, where it forms biomolecular condensates, separate from the TFIID complex. Quantitative mass spectrometry analyses reveal that the TAF2 IDR is required for the interaction with the nuclear speckle and spliceosome-associated protein SRRM2, which is thereby recruited to TFIID. The formation of SRRM2-free TFIID complexes elicits a set of unique alternative splicing events. These include events in RNAs coding for proteins involved in transcription and transmembrane transport. Together, these data identify an IDR of the basal transcription machinery as a molecular switch between nuclear compartments to control protein complex composition and pre-mRNA splicing.
2024-04-26 | PXD049117 | Pride