Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition and tumorigenesis of non-small cell lung cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE100347 | GEO | 2018/07/01
REPOSITORIES: GEO
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Project description:The histone variant H2A.Z is essential for maintaining the identity of embryonic stem cell (ESC) by keeping bivalent developmental genes at a poised state. However, how H2A.Z is deposited into the bivalent domains remains unknown. In mammals, two chromatin-remodeling complexes, Tip60/p400 and SRCAP, exchange the canonical histone H2A for H2A.Z in the chromatin. Here we show that Glioma Amplified Sequence 41 (Gas41), a shared subunit of the two H2A.Z-depositing complexes, functions as a reader of histone acetylation and recruits Tip60/p400 and SRCAP to deposit H2A.Z into specific chromatin regions including bivalent domains. The YEATS domain of Gas41 bound to acetylation on histone H3K27 and H3K14 both in vitro and in cells. Crystal structure of the Gas41 YEATS domain in complex with the H3K27ac peptide revealed that, similar to the AF9 and ENL YEATS domains, Gas41 YEATS forms a serine-lined aromatic cage for Kac recognition; mutations of either the aromatic residues of YEATS domain or the nearby residue of H3K27 abrogated the interaction. In mESCs, knockdown of Gas41 led to cell differentiation as the result of derepression of differentiation genes. Importantly, the differentiated morphology was rescued by expressing wild type Gas41, but not the YEATS domain mutated counterparts that do not recognize histone acetylation. Mechanically, we found that Gas41 depletion led to reduction of H2A.Z levels and a concomitant reduction of H3K27me3 levels at the promoters of a subset of bivalent genes. Together, our study identifies the Gas41 YEATS domain as a reader of histone acetylation and establishes a link between histone acetylation and H2A.Z deposition in the maintenance of ESC identity.
2018-07-01 | GSE100460 | GEO
Project description:Cancer cells are characterized by aberrant epigenetic landscapes and often exploit the chromatin machinery to activate oncogenic gene expression programs1. The recognition of modified histones by “reader” proteins constitutes a key mechanism underlying these processes; therefore targeting such pathways holds clinical promise, as exemplified by the recent development of BET bromodomain inhibitors2,3. We recently identified the YEATS domain as a novel acetyllysine-binding module4, yet its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralog AF9, is required for disease maintenance in a variety of acute myeloid leukaemias (AML). CRISPR-Cas9 mediated depletion of ENL led to anti-leukemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies in vitro and ChIP-seq analyses in leukaemia cells revealed that ENL binds to acetylated histone H3, and colocalizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemias. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced RNA polymerase II recruitment on ENL target genes, thus leading to suppression of oncogenic gene expression programs. Importantly, disruption of ENL’s functionality further sensitized leukaemia cells to BET inhibitors. Together, our study identifies ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in AML and suggests that displacement of ENL from chromatin is a promising epigenetic therapy alone or in combination with BET inhibitors for AML
2017-04-05 | GSE80774 | GEO
Project description:Cancer cells are characterized by aberrant epigenetic landscapes and often exploit the chromatin machinery to activate oncogenic gene expression programs1. The recognition of modified histones by “reader” proteins constitutes a key mechanism underlying these processes; therefore targeting such pathways holds clinical promise, as exemplified by the recent development of BET bromodomain inhibitors2,3. We recently identified the YEATS domain as a novel acetyllysine-binding module4, yet its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralog AF9, is required for disease maintenance in a variety of acute myeloid leukaemias (AML). CRISPR-Cas9 mediated depletion of ENL led to anti-leukemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies in vitro and ChIP-seq analyses in leukaemia cells revealed that ENL binds to acetylated histone H3, and colocalizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemias. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced RNA polymerase II recruitment on ENL target genes, thus leading to suppression of oncogenic gene expression programs. Importantly, disruption of ENL’s functionality further sensitized leukaemia cells to BET inhibitors. Together, our study identifies ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in AML and suggests that displacement of ENL from chromatin is a promising epigenetic therapy alone or in combination with BET inhibitors for AML
2017-02-23 | GSE80779 | GEO
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:Recognition of modified histones by “reader” proteins constitutes a key mechanism regulating diverse chromatin-associated processes important for normal and neoplastic development. For instance, bromodomain-containing proteins bind to acetylated histones and regulate chromatin dynamics and gene expression. We recently identified the YEATS domain as a novel acetyllysine-binding module; however, the functional importance of YEATS domain-containing proteins in human cancer remains largely unknown. Here we show that the YEATS2 gene is highly amplified in human non-small cell lung cancer (NSCLC) and is required for cancer cell growth and survival. Biochemical and crystal structural studies show that YEATS2 binds to acetylated histone H3, and the YEATS domain utilizes a serine-lined aromatic “sandwiching” cage for acetyllysine readout. ChIP-seq analyses in lung cancer cells reveal that the YEATS2-containing ATAC complex colocalizes with H3K27 acetylation (H3K27ac) on the promoters of actively transcribed genes. Depletion of YEATS2 or disruption of the interaction between its YEATS domain and acetylated histones reduces the ATAC complex-dependent promoter H3K9ac levels and deactivates the expression of essential genes, including the ribosomal protein-encoding genes, which are important for cancer cell growth and survival. Taken together, our study identifies YEATS2 as a histone H3K27ac specific reader that regulates a transcriptional program essential for NSCLC tumorigenesis.
2017-10-31 | GSE90781 | GEO
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.
2020-12-04 | GSE162592 | GEO
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.
2020-12-04 | GSE162591 | GEO
Project description:We previously identified the YEATS domain-containing protein ENL as a reader of histone acetylation. Recently, hotspot mutations in ENL were frequently found in Wilms’ tumor, the most common type of pediatric kidney cancer. Here, we report that these cancer-associated mutations in the ENL YEATS domain confer gain of functions in transcriptional control and impair kidney differentiation by driving self-reinforced chromatin targeting. Ectopic expression of ENL mutants in kidney cell lines resulted in transcriptional changes of genes enriched in embryonic nephron progenitors and Wilms’ tumor. When tested in a nephrogenesis assay, ENL mutant expression led to undifferentiated structures resembling those observed in human Wilms’ tumor. Genome-wide analyses revealed that while mutant ENL bound to largely similar genomic loci as wild-type ENL, they exhibited increased occupancy at a subset of targets, including developmentally critical genes such as the HOXA cluster. The cancer-associated mutations enabled self-reinforced recruitment of ENL on chromatin by promoting self-association, resulting in the formation of discrete nuclear puncta that are characteristic of phase-separated biomolecular condensates. Enhanced occupancy of ENL mutants led to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Collectively, our studies represent, to our knowledge, the first discovery that cancer-associated mutations in a chromatin reader drive self-reinforced chromatin targeting, which in turns, perturbs developmental programs and derails normal cell fate control during mammalian development towards an oncogenic path.
2020-01-03 | GSE125186 | GEO
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:Histone lysine acetylation and methylation regulate gene transcription through coordination of chromatin structure and transcriptional activity. However, our understanding of the role of histones in gene regulation is far from complete, in part due to newly discovered novel histone modifications, whose functions are yet to be uncovered1. Here we report that histone H3 lysine 27 crotonylation (H3K27cr) is selectively recognized by the YEATS domain of GAS41 in association with SIN3a-HDAC1/2 co-repressor complex for gene transcriptional repression. The GAS41 YEATS domain dimer binds proto-oncogenic transcription factor c-Myc, which recruits GAS41/SIN3a-HDAC1/2 complex to target gene loci in chromatin such as cell cycle inhibitor p21. Transcriptional de-repression of p21, directed by tumor suppressor p53 upon doxorubicin stimulation, entails dissociation of c-Myc/GAS41/SIN3a-HDAC1/2 complex from chromatin, reduced H3K27 crotonylation, and consequentially increased H3K27 acetylation at p21 locus. GAS41 knockout or H3K27cr binding depletion with CRISPR/Cas9 results in p21 activation, cell cycle arrest and tumor growth inhibition in mice. Our study explains mechanistically causal effect of GAS41 and c-Myc gene amplification on down-regulation of p21 in human colorectal cancer, and suggests GAS41 as an anti-cancer target. We propose that H3K27 crotonylation represents a previously unrecognized, distinct chromatin state for gene transcriptional repression in contrast to H3K27 trimethylation for long-term transcriptional silencing and H3K27 acetylation for transcriptional activation.
2023-10-03 | GSE128590 | GEO