Similar Datasets
Project description:The non-canonical BAF complex (ncBAF) subunit BRD9 is essential for acute myeloid leukemia (AML) cell viability but has an unclear role in leukemogenesis. Because BRD9 is required for ncBAF complex assembly through its DUF3512 domain, precise bromodomain inhibition is necessary to parse the role of BRD9 as a transcriptional regulator from that of a scaffolding protein. To understand the role of BRD9 bromodomain function in regulating AML, we selected a panel of five AML cell lines with distinct driver mutations, disease classifications, and genomic aberrations and subjected these cells to short-term BRD9 bromodomain inhibition. We examined the bromodomain-dependent growth of these cell lines, identifying a dependency in AML cell lines but not HEK293T cells. To define a mechanism through which BRD9 maintains AML cell survival, we examined nascent transcription, chromatin accessibility, and ncBAF complex binding genome-wide after bromodomain inhibition. We identified extensive regulation of transcription by BRD9 bromodomain activity, including repression of myeloid maturation factors and tumor suppressor genes, while standard AML chemotherapy targets were repressed by inhibition of the BRD9 bromodomain. BRD9 bromodomain activity maintained accessible chromatin at both gene promoters and gene-distal putative enhancer regions, in a manner that qualitatively correlated with enrichment of BRD9 binding. Furthermore, we identified reduced chromatin accessibility at GATA, ETS, and AP-1 motifs and increased chromatin accessibility at SNAIL-, HIC-, and TP53-recognized motifs after BRD9 inhibition. These data suggest a role for BRD9 in regulating AML cell differentiation through modulation of accessibility at hematopoietic transcription factor binding sites.SignificanceThe bromodomain-containing protein BRD9 is essential for AML cell viability, but it is unclear whether this requirement is due to the protein's role as an epigenetic reader. We inhibited this activity and identified altered gene-distal chromatin regulation and transcription consistent with a more mature myeloid cell state.
| S-EPMC10831031 | biostudies-literature
Project description:The non-canonical BAF complex (ncBAF) subunit BRD9 is essential for acute myeloid leukemia (AML) cell viability but has an unclear role in leukemogenesis. Because BRD9 is required for ncBAF complex assembly through its DUF3512 domain, precise bromodomain inhibition is necessary to parse the role of BRD9 as a transcriptional regulator from that of a scaffolding protein. To understand the specific role of BRD9 bromodomain function in regulating AML, we selected a panel of five AML cell lines with distinct driver mutations, disease classifications, and genomic aberrations and subjected them to short-term BRD9 bromodomain inhibition. We characterized the bromodomain-dependent growth of these cell lines, identifying a dependency in AML cell lines but not HEK293T cells. To define a mechanism through which BRD9 maintains AML cell survival, we examined nascent transcription, chromatin accessibility, and ncBAF complex binding genome-wide after bromodomain inhibition. We identified extensive regulation of transcription by BRD9 bromodomain activity, including repression of myeloid maturation factors and tumor suppressor genes, while standard AML chemotherapy targets (Bcl2, Btk, Kit) were repressed by inhibition of the BRD9 bromodomain. BRD9 bromodomain activity maintained accessible chromatin at both gene promoters and gene-distal putative enhancer regions, in a manner that qualitatively correlated with enrichment of BRD9 binding. Furthermore, we identified reduced chromatin accessibility at GATA, ETS, and AP-1 motifs and increased chromatin accessibility at SNAIL-, HIC-, and TP53-recognized motifs after BRD9 inhibition. We interpret these data as signifying a role for BRD9 in regulating the differentiation block that is common to all AML subtypes through modulation of accessibility at hematopoietic transcription factor binding sites.
2023-10-20 | GSE241427 | GEO
Project description:The non-canonical BAF complex (ncBAF) subunit BRD9 is essential for acute myeloid leukemia (AML) cell viability but has an unclear role in leukemogenesis. Because BRD9 is required for ncBAF complex assembly through its DUF3512 domain, precise bromodomain inhibition is necessary to parse the role of BRD9 as a transcriptional regulator from that of a scaffolding protein. To understand the specific role of BRD9 bromodomain function in regulating AML, we selected a panel of five AML cell lines with distinct driver mutations, disease classifications, and genomic aberrations and subjected them to short-term BRD9 bromodomain inhibition. We characterized the bromodomain-dependent growth of these cell lines, identifying a dependency in AML cell lines but not HEK293T cells. To define a mechanism through which BRD9 maintains AML cell survival, we examined nascent transcription, chromatin accessibility, and ncBAF complex binding genome-wide after bromodomain inhibition. We identified extensive regulation of transcription by BRD9 bromodomain activity, including repression of myeloid maturation factors and tumor suppressor genes, while standard AML chemotherapy targets (Bcl2, Btk, Kit) were repressed by inhibition of the BRD9 bromodomain. BRD9 bromodomain activity maintained accessible chromatin at both gene promoters and gene-distal putative enhancer regions, in a manner that qualitatively correlated with enrichment of BRD9 binding. Furthermore, we identified reduced chromatin accessibility at GATA, ETS, and AP-1 motifs and increased chromatin accessibility at SNAIL-, HIC-, and TP53-recognized motifs after BRD9 inhibition. We interpret these data as signifying a role for BRD9 in regulating the differentiation block that is common to all AML subtypes through modulation of accessibility at hematopoietic transcription factor binding sites.
2023-10-20 | GSE241425 | GEO
Project description:The non-canonical BAF complex (ncBAF) subunit BRD9 is essential for acute myeloid leukemia (AML) cell viability but has an unclear role in leukemogenesis. Because BRD9 is required for ncBAF complex assembly through its DUF3512 domain, precise bromodomain inhibition is necessary to parse the role of BRD9 as a transcriptional regulator from that of a scaffolding protein. To understand the specific role of BRD9 bromodomain function in regulating AML, we selected a panel of five AML cell lines with distinct driver mutations, disease classifications, and genomic aberrations and subjected them to short-term BRD9 bromodomain inhibition. We characterized the bromodomain-dependent growth of these cell lines, identifying a dependency in AML cell lines but not HEK293T cells. To define a mechanism through which BRD9 maintains AML cell survival, we examined nascent transcription, chromatin accessibility, and ncBAF complex binding genome-wide after bromodomain inhibition. We identified extensive regulation of transcription by BRD9 bromodomain activity, including ATACseq_Repression of myeloid maturation factors and tumor suppressor genes, while standard AML chemotherapy targets (Bcl2, Btk, Kit) were ATACseq_Repressed by inhibition of the BRD9 bromodomain. BRD9 bromodomain activity maintained accessible chromatin at both gene promoters and gene-distal putative enhancer regions, in a manner that qualitatively correlated with enrichment of BRD9 binding. Furthermore, we identified reduced chromatin accessibility at GATA, ETS, and AP-1 motifs and increased chromatin accessibility at SNAIL-, HIC-, and TP53-recognized motifs after BRD9 inhibition. We interpret these data as signifying a role for BRD9 in regulating the differentiation block that is common to all AML subtypes through modulation of accessibility at hematopoietic transcription factor binding sites.
2023-10-20 | GSE241424 | GEO
Project description:The ncBAF complex regulates transcription in AML through H3K27ac sensing by BRD9
| PRJNA1008139 | ENA
Project description:The ncBAF complex regulates transcription in AML through H3K27ac sensing by BRD9 (CUT&Run)
| PRJNA1008145 | ENA
Project description:The ncBAF complex regulates transcription in AML through H3K27ac sensing by BRD9 (ATAC-Seq)
| PRJNA1008142 | ENA
Project description:The ncBAF complex regulates transcription in AML through H3K27ac sensing by BRD9 (TT-Seq)
| PRJNA1008144 | ENA
Project description:Several long non-coding RNAs (lncRNAs) have been reported regulate the expression of neighbor protein-coding genes at post-transcriptional, transcriptional and epigenetic levels. Dmp1 (Dentin matrix protein 1), encoding a non-collagenous extracellular matrix protein, plays an important role in dentin and bone mineralization. However, the transcriptional regulation of lncRNA on Dmp1 has not been reported. In this study, we identified a novel lncRNA named lnc-DMP1, which is near the Dmp1 gene region and undergoes remarkable changes during mandible development. lnc-DMP1 is co-localized and significantly expressed correlation with Dmp1 in embryonic and postnatal mouse mandibles. In MC3T3-E1 cells, lnc-DMP1 positively regulates DMP1 expression and skeletal mineralization. Furthermore, lnc-DMP1 induces the promoter activity of Dmp1 by modulating H3K27Ac enrichment in the Dmp1 promoter. In conclusion, our results indicate that lnc-DMP1 is a novel lncRNA near the Dmp1 gene region and regulates Dmp1 expression by modulating the H3K27 acetylation level of Dmp1 promoter.
| S-EPMC7093497 | biostudies-literature
Project description:Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no discernible function in hematopoietic stem cells (HSCs). In mouse models of acute myeloid leukemia (AML), loss of G9a significantly delays disease progression and reduces leukemia stem cell (LSC) frequency. We connect this function of G9a to its methyltransferase activity and its interaction with the leukemogenic transcription factor HoxA9 and provide evidence that primary human AML cells are sensitive to G9A inhibition. Our results highlight a clinical potential of G9A inhibition as a means to counteract the proliferation and self-renewal of AML cells by attenuating HoxA9-dependent transcription.
| S-EPMC3937511 | biostudies-literature