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Phase separation mediates AKAP95 regulating oncogenic MLL-fusion driven transcription and its application in leukemia therapy (ChIP-Seq)

ABSTRACT: Oncogenic transcription represents a crucial event in MLL rearranged (MLLr) leukemia, yet the precise role of transcription co-activators in MLL-fusion protein-associated transcription and their contribution to leukemogenesis remain incompletely understood. Here, we demonstrate that AKAP95 is notably up-regulated in both MLLr patients and in MLL-AF9-transformed mouse bone marrow. AKAP95 proves essential for initiating mouse MLL-AF9 leukemia, exhibiting widespread DNA binding across the genome, particularly at gene promoters. Interaction with the translocated MLL1 fragment primarily occurs through phase separation mechanisms. AKAP95's RNA-binding properties, coupled with its phase separation behavior, govern its binding to pre-mRNA and concurrent transcriptional regulation. Importantly, we engineered a peptide to disrupt its phase separation, effectively attenuating AKAP95-mediated transcriptional co-activation and inhibiting the growth of MLLr cell lines. These findings illustrate a vivid example of an RNA-binding protein orchestrating transcription and tumorigenesis via phase separation, underscoring the potential for targeting oncogenic condensation mechanisms therapeutically.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271854 | GEO | 2025/11/11

REPOSITORIES: GEO

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Phase separation mediates AKAP95 regulating oncogenic MLL-fusion driven transcription and its application in leukemia therapy (PRO-Seq)

Project description:Oncogenic transcription represents a crucial event in MLL rearranged (MLLr) leukemia, yet the precise role of transcription co-activators in MLL-fusion protein-associated transcription and their contribution to leukemogenesis remain incompletely understood. Here, we demonstrate that AKAP95 is notably up-regulated in both MLLr patients and in MLL-AF9-transformed mouse bone marrow. AKAP95 proves essential for initiating mouse MLL-AF9 leukemia, exhibiting widespread DNA binding across the genome, particularly at gene promoters. Interaction with the translocated MLL1 fragment primarily occurs through phase separation mechanisms. AKAP95's RNA-binding properties, coupled with its phase separation behavior, govern its binding to pre-mRNA and concurrent transcriptional regulation. Importantly, we engineered a peptide to disrupt its phase separation, effectively attenuating AKAP95-mediated transcriptional co-activation and inhibiting the growth of MLLr cell lines. These findings illustrate a vivid example of an RNA-binding protein orchestrating transcription and tumorigenesis via phase separation, underscoring the potential for targeting oncogenic condensation mechanisms therapeutically.

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Phase separation mediates AKAP95 regulating oncogenic MLL-fusion driven transcription and its application in leukemia therapy (CLIP-Seq)

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The MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in MLLr AML

Project description:In MLL-rearranged (MLLr) leukemias the N terminal part of the MLL gene can be fused to over 60 different partner genes. Here, we investigate the genome wide binding of the MLL-AF9 and MLL-AF4 fusion proteins and their epigenetic signatures in order to define a core set of MLLr targets. We uncover both common as well as specific MLL-AF9 and MLL-AF4 target genes, which are all marked by H3K79me2, H3K27ac, and H3K4me3. Apart from promoter binding, we also identify MLL-AF9 and MLL-AF4 binding at specific subsets of non overlapping active distal regulatory elements. Despite this differential enhancer binding MLL-AF9 and MLL-AF4 still share a common gene program, which represents part of the RUNX1 gene program and constitutes of CD34+ and monocyte specific genes. Comparing these datasets revealed several zinc finger transcription factors as potential MLL-AF9 co-regulators. Together these results suggest that MLL-fusions collaborate with specific subsets of TFs to aberrantly regulate the RUNX1 gene program in 11q23 AMLs.

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Regulation of transcription by MLL2 complex and MLL complexes-associated protein AKAP95

Project description:Although histone H3 lysine 4 (H3K4) methylation is widely associated with gene activation, direct evidence for its causal role in transcription, through specific MLL family members, is scarce. Here we have purified a human MLL2 (Kmt2b) complex that is highly active in H3K4 methylation and chromatin transcription in a cell-free system. This effect requires SAM and intact H3K4, establishing a direct and causal role for MLL2-mediated H3K4 methylation in transcription. We then show that human AKAP95, a chromatin-associated protein, is physically and functionally associated with the Dpy-30-MLL complexes and directly enhances their methyltransferase activity. Ectopic AKAP95 stimulates expression of a chromosomal reporter in synergy with MLL1 or MLL2, whereas AKAP95 depletion impairs retinoic acid-mediated gene induction in embryonic stem cells. These results demonstrate an important role for AKAP95 in regulating histone methylation and gene expression, particularly during cell fate transitions. Total RNAs from control or knockdown cells before and after RA-mediated differentiation were subjected to Illumina microarray analyses. The complete dataset containing non_normalized, median-normalized and expression ratio (relative to Scramble shRNA, undifferentiated data) is linked below as a supplementary file [complete_data.txt].

2013-07-01 | E-GEOD-48128 | biostudies-arrayexpress

Regulation of transcription by MLL2 complex and MLL complexes-associated protein AKAP95

2013-07-01 | GSE48128 | GEO

Phase separation mediates AKAP95 regulating oncogenic MLL-fusion driven transcription and its application in leukemia therapy

Project description:Phase separation mediates AKAP95 regulating oncogenic MLL-fusion driven transcription and its application in leukemia therapy

| PRJNA1133755 | ENA

AKAP95 regulates splicing through scaffolding RNAs and RNA processing factors

Project description:Alternative splicing of pre-mRNAs significantly contributes to the complexity of gene expression in higher organisms, but the regulation of the splice site selection remains incompletely understood. We have previously demonstrated that a chromatin-associated protein, AKAP95 (AKAP8), has a remarkable activity in enhancing chromatin transcription. In this study, we have shown that AKAP95 physically interacts with many factors involved in transcription and RNA processing, and functionally regulates pre-mRNA splicing. AKAP95 directly promotes splicing in vitro and the inclusion of a specific exon of an endogenous gene FAM126A. The N-terminal YG-rich domain of AKAP95 is important for its binding to RNA processing factors including selective groups of hnRNP proteins, and its zinc finger domains are critical for pre-mRNA binding. Genome-wide binding assays revealed that AKAP95 bound preferentially to proximal intronic regions on a large number of pre-mRNAs in human transcriptome, and AKAP95 depletion predominantly resulted in reduced inclusion of many exons. AKAP95 also selectively coordinates with hnRNP H/F and U proteins in regulating alternative splicing events. We have further shown that AKAP95 directly interacts with itself. Taken together, our results establish AKAP95 as a novel and mostly positive regulator of pre-mRNA splicing and a possible integrator of transcription and splicing regulation, and support a model that AKAP95 regulates pre-mRNA splicing via through scaffolding RNAs and RNA processing factors and facilitating the splice site communication.

2016-09-08 | GSE81916 | GEO

Phase separation mediates AKAP95 regulating oncogenic MLL-fusion driven transcription and its application in leukemia therapy (CLIP-Seq)

Project description:Phase separation mediates AKAP95 regulating oncogenic MLL-fusion driven transcription and its application in leukemia therapy (CLIP-Seq)

| PRJNA1133758 | ENA

Phase separation mediates AKAP95 regulating oncogenic MLL-fusion driven transcription and its application in leukemia therapy (ChIP-Seq)

Project description:Phase separation mediates AKAP95 regulating oncogenic MLL-fusion driven transcription and its application in leukemia therapy (ChIP-Seq)

| PRJNA1133759 | ENA

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