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Epigenomic mapping in B-cell acute lymphoblastic leukemia identifies transcriptional regulators and noncoding variants promoting distinct chromatin architectures [CUT&RUN]

ABSTRACT: B-cell lineage acute lymphoblastic leukemia (B-ALL) is comprised of diverse molecular subtypes and while transcriptional and DNA methylation profiling of B-ALL subtypes has been extensively examined, the accompanying chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq for 10 B-ALL molecular subtypes in primary ALL cells from 154 patients. Comparisons with B-cell progenitors identified candidate B-ALL cell-of-origin and AP-1-associated cis-regulatory rewiring in B-ALL. Cis-regulatory rewiring promoted B-ALL-specific gene regulatory networks impacting oncogenic signaling pathways that perturb normal B-cell development. We also identified that over 20% of B-ALL accessible chromatin sites exhibit strong subtype enrichment, with transcription factor (TF) footprint profiling identifying candidate TFs that maintain subtype-specific chromatin architectures. Over 9000 inherited genetic variants were further uncovered that contribute to variability in chromatin accessibility among individual patient samples. Overall, our data suggest that distinct chromatin architectures are driven by diverse TFs and inherited genetic variants which promote unique gene regulatory networks that contribute to transcriptional differences among B-ALL subtypes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226399 | GEO | 2023/10/17

REPOSITORIES: GEO

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Project description:Acute lymphoblastic leukemia (ALL) is the most common malignancy in pediatric patients and represents about a quarter of all pediatric malignancies. Past work has characterized B-cell lineage ALL (B-ALL) into molecular subtypes spanning a range of aberrant chromosomal rearrangements and chimeric fusions driving malignancy. While transcriptional and DNA methylation profiling of these subtypes has been extensively examined, the accompanying chromatin landscape and corresponding gene regulatory repertoire is not well characterized for many B-ALL subtypes. To better understand the B-ALL epigenome and gene regulatory network we mapped chromatin accessibility for 11 B-ALL molecular subtypes using assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) across 154 primary patient samples. We uncovered extensive chromatin reprogramming between B-ALL and primary B-cells that drive oncogenic signaling pathways and perturb normal B-cell functions. Strikingly, we also identified 42,457 accessible chromatin sites which exhibit strong subtype enrichment. Subtype enriched sites were shown to have a subtype prediction cross-validation accuracy of nearly 90% within a PCA-LDA classification model framework. Transcription factor (TF) footprint profiling and transcriptomic information further identified candidate subtype-specific driver TFs as well as unique gene regulatory networks among B-ALL subtypes. To better understand how genetic variation impacts chromatin accessibility, we identified 9080 variants that act as ATAC-seq chromatin accessibility quantitative trait loci (ATAC-QTLs) and contribute to chromatin accessibility variability among patient samples. Overall, this large dataset and associated analyses offer a unique window into the gene regulatory landscape of B-ALL that highlight the complexity and heterogeneity of chromatin accessibility among B-ALL molecular subtypes. Keywords: Genome binding/occupancy profiling by high throughput sequencing

Project description:Developmental programs are implemented by regulatory interactions between Transcription Factors (TFs) and their target genes, which remain yet poorly understood. While recent studies have focused on regulatory cascades of TFs that govern early development, little is known on how these are selected and controlled the ultimate cellular effectors of terminal differentiation. We addressed this question during late Drosophila embryogenesis when the finely tuned expression of a TF, Ovo/Shavenbaby (Svb), triggers the morphological differentiation of epidermal trichomes. We used chromatin immunoprecipitation and microarray profiling to identify Svb downstream target genes and show that Svb directly regulates a large set of terminal effectors of trichome formation. Functional assays delineated 18 Svb bound sequences driving specific expression of trichome effectors, with highly similar pattern and dynamics. Coupling computational modeling to functional dissection, we further investigated the regulatory logic of these enhancers. We find that these “terminal” enhancers harbor remarkable features with respect to their functional architectures. Trichome enhancers display weak if any clustering of Svb binding sites. Moreover, the in vivo function of each site relies on its intimate context, with a critical importance of the nucleotides flanking Svb binding sites. Finally, we identify additional cis-regulatory motifs, showing a broad diversity of positioning among trichome enhancers, and that critically contribute to their activity. Taken together, these results show that trichome formation is underpinned by unexpectedly diverse modes of regulation, and shed light on the functional architecture of enhancers governing a terminal differentiation program. Chromatin from 12-14 hour old embryos expressing svb tagged with GFP (Kondo T, Plaza S, Zanet J, Benrabah E, Valenti P, Hashimoto Y, Kobayashi S, Payre F, Kageyama Y: Small peptides switch the transcriptional activity of Shavenbaby during Drosophila embryogenesis. Science 2010, 329:336-339) was collected in duplicate. Chromatin was immunoprecipitated using an antiGFP antibody and input chromatin was used as a control.

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Epigenomic mapping in B-cell acute lymphoblastic leukemia identifies transcriptional regulators and noncoding variants promoting distinct chromatin architectures [CUT&RUN]

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