AF9/MLLT3 ChIP-Seq in LPS-stimulated RAW264.7 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE76539 | GEO | 2016/04/21
SECONDARY ACCESSION(S): PRJNA307672
REPOSITORIES: GEO
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Project description:The recognition of modified histones by “reader” proteins constitutes a key mechanism regulating gene expression in the chromatin context. Compared with the great variety of readers for histone methylation, few protein modules that recognize histone acetylation are known. Here we show that the evolutionarily conserved YEATS domains constitute a novel family of acetyllysine readers. The human AF9 YEATS domain binds strongly to histone H3K9 acetylation and, to a lesser extent, H3K27 and H3K18 acetylation. Crystal structural studies revealed that AF9 YEATS adopts an eight-stranded immunoglobin fold and utilizes a serine-lined aromatic “sandwiching” cage for acetyllysine readout, representing a novel recognition mechanism that is distinct from that of known acetyllysine readers. Histone acetylation recognition by AF9 is important for the chromatin recruitment of the H3K79 methyltransferase DOT1L. Together, our studies identify the YEATS domain as a novel acetyllysine-binding module, thereby establishing the first direct link between histone acetylation and DOTL1-mediated H3K79 methylation in transcription control. ChIP-seq analysis of AF9, H3K79me3, H3K9ac in Hela cells and H3K79me3 in Hela AF9 knockdown and Hela Dot1L knockdown cells.
2014-12-11 | E-GEOD-60366 | biostudies-arrayexpress
Project description:The recognition of modified histones by “reader” proteins constitutes a key mechanism regulating gene expression in the chromatin context. Compared with the great variety of readers for histone methylation, few protein modules that recognize histone acetylation are known. Here we show that the evolutionarily conserved YEATS domains constitute a novel family of acetyllysine readers. The human AF9 YEATS domain binds strongly to histone H3K9 acetylation and, to a lesser extent, H3K27 and H3K18 acetylation. Crystal structural studies revealed that AF9 YEATS adopts an eight-stranded immunoglobin fold and utilizes a serine-lined aromatic “sandwiching” cage for acetyllysine readout, representing a novel recognition mechanism that is distinct from that of known acetyllysine readers. Histone acetylation recognition by AF9 is important for the chromatin recruitment of the H3K79 methyltransferase DOT1L. Together, our studies identify the YEATS domain as a novel acetyllysine-binding module, thereby establishing the first direct link between histone acetylation and DOTL1-mediated H3K79 methylation in transcription control.
2014-12-11 | GSE60366 | GEO
Project description:Ligands activation of RXR modulate host antivarl response. We used microarray to determine if 9cRA could regulate the antiviral gene expression in LPS- and polyI:C triggered RAW264.7 cells. RAW 264.7 cells were pre-treated with DMSO or 100nM of 9cis-retinoic acid for 16hours. The cells were then stimulated with polyI:C (6ug transfected) or LPS (500ng/mL) for 2 hours.
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Project description:Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia
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Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to evaluate the gene expression of E4BP4 knockout (KO) RAW264.7 cells. Methods: We generated E4BP4-KO RAW264.7 Cell Line using CRISPR-CAS9 system. Control plasmid was encoding the Cas9 nuclease without gRNA sequence. Total RNA of E4BP4-KO and Control (CTRL) RAW264.7 cells was extracted. RAW264.7 cells RNA profiles were generated by deep sequencing for two groups (E4BP4-KO versus CTRL RAW264.7 cells) with three samples each. Results: There were significant differences between E4BP4-KO and CTRL RAW264.7 cells. Conclusions: Deletion of E4BP4 in RAW264.7 cells induced various changes at the transcription level.
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Project description:Transcriptional co-regulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional co-activator, ENL, as a selective requirement for the survival of acute leukemia – particularly those driven by multiple lineage leukemia (MLL)-fusion oncogenes. The YEATS domain of ENL, which binds to chromatin by interacting with acyl-lysine side chains, is critical for its pathogenic function in acute leukemiaand highlighted an essential role for its chromatin reader YEATS domain. Motivated by these recent discoveries, we executed a screen of nearly 300,000 small molecules to identify chromatin-competitiveand identified an amido-imidazopyridine inhibitors of the ENL YEATS domain (IC50 = 7 µM). Leveraging a SuFEx-based high-throughput approach to Optimizing an amido-imidazopyridine scaffold with highly parallelized, SuFEx-based medicinal chemistry optimization, we discovered SR-0813 (IC50 = 25 nM), a potent and selective ENL/AF9 YEATS domain inhibitor that exclusively inhibits the growth of ENL-dependent leukemia cell lines. Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the response of AML cells to pharmacological ENL disruption for the first time. Most notably, displacement of In AML cells, SR-0813 evicts ENL from chromatin, by SR-0813 preferentially suppresseselicited a strikingly selective suppression of ENL target genes, including HOXA9/10, MYB, MYC and a number of other leukemia proto-oncogenes. Our study reproduces a number of key observations previously made by CRISPR/Cas9 loss of function and dTAG-mediated degradation, and therefore, both reinforces ENL as an emerging leukemia target and validates SR-0813 as a high-quality chemical probe.
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Project description:Transcriptional co-regulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional co-activator, ENL, as a selective requirement for the survival of acute leukemia – particularly those driven by multiple lineage leukemia (MLL)-fusion oncogenes. The YEATS domain of ENL, which binds to chromatin by interacting with acyl-lysine side chains, is critical for its pathogenic function in acute leukemiaand highlighted an essential role for its chromatin reader YEATS domain. Motivated by these recent discoveries, we executed a screen of nearly 300,000 small molecules to identify chromatin-competitiveand identified an amido-imidazopyridine inhibitors of the ENL YEATS domain (IC50 = 7 µM). Leveraging a SuFEx-based high-throughput approach to Optimizing an amido-imidazopyridine scaffold with highly parallelized, SuFEx-based medicinal chemistry optimization, we discovered SR-0813 (IC50 = 25 nM), a potent and selective ENL/AF9 YEATS domain inhibitor that exclusively inhibits the growth of ENL-dependent leukemia cell lines. Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the response of AML cells to pharmacological ENL disruption for the first time. Most notably, displacement of In AML cells, SR-0813 evicts ENL from chromatin, by SR-0813 preferentially suppresseselicited a strikingly selective suppression of ENL target genes, including HOXA9/10, MYB, MYC and a number of other leukemia proto-oncogenes. Our study reproduces a number of key observations previously made by CRISPR/Cas9 loss of function and dTAG-mediated degradation, and therefore, both reinforces ENL as an emerging leukemia target and validates SR-0813 as a high-quality chemical probe.
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Project description:Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia [RNA-Seq]
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