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Epigenomic mapping reveals distinct B cell acute lymphoblastic leukemia chromatin architectures and regulators.

ABSTRACT: B cell lineage acute lymphoblastic leukemia (B-ALL) is composed of diverse molecular subtypes, and while transcriptional and DNA methylation profiling has been extensively examined, the chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq in primary B-ALL cells from 156 patients spanning ten molecular subtypes and present this dataset as a resource. Differential chromatin accessibility and transcription factor (TF) footprint profiling were employed and identified B-ALL cell of origin, TF-target gene interactions enriched in B-ALL, and key TFs associated with accessible chromatin sites preferentially active in B-ALL. We further identified over 20% of accessible chromatin sites exhibiting strong subtype enrichment and candidate TFs that maintain subtype-specific chromatin architectures. Over 9,000 genetic variants were uncovered, contributing to variability in chromatin accessibility among patient samples. Our data suggest that distinct chromatin architectures are driven by diverse TFs and inherited genetic variants that promote unique gene-regulatory networks.

SUBMITTER: Barnett KR

PROVIDER: S-EPMC10726428 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Epigenomic mapping reveals distinct B cell acute lymphoblastic leukemia chromatin architectures and regulators.

Barnett Kelly R KR Mobley Robert J RJ Diedrich Jonathan D JD Bergeron Brennan P BP Bhattarai Kashi Raj KR Monovich Alexander C AC Narina Shilpa S Yang Wenjian W Crews Kristine R KR Manring Christopher S CS Jabbour Elias E Paietta Elisabeth E Litzow Mark R MR Kornblau Steven M SM Stock Wendy W Inaba Hiroto H Jeha Sima S Pui Ching-Hon CH Mullighan Charles G CG Relling Mary V MV Pruett-Miller Shondra M SM Ryan Russell J H RJH Yang Jun J JJ Evans William E WE Savic Daniel D

Cell genomics 20231120 12

B cell lineage acute lymphoblastic leukemia (B-ALL) is composed of diverse molecular subtypes, and while transcriptional and DNA methylation profiling has been extensively examined, the chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq in primary B-ALL cells from 156 patients spanning ten molecular subtypes and present this dataset as a resource. Differential chromatin accessibility and transcription factor (TF) footprint ...[more]

PMID: 38116118

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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:DNA methylation appears to play an essential mechanistic role in the pathogenesis of ALL, thereby potentiate its use as a biomarker for diagnosis and prognosis (Milani, Lundmark et al. 2010; Geng, Brennan et al. 2012; Sandoval, Heyn et al. 2013), and even a potential target of novel therapeutic approaches in ALL. In present study, we collected blood specimens for 4 pairs of monozygotic twins (MZ) and 1 pair of dizygotic twin (DZ) that are discordant for ALL. We sought to comprehensively assess the magnitude of genetic and epigenetic differences between ALL-affected and unaffected twins. we conducted whole genome and whole methylome sequencing on these five pairs of ALL-discordant twins. We also examined both the MZ and DZ twins using whole-genome bisulfite sequencing (WGBS). At first, the methylation differences across the genome were addressed globally by Circos software. And then tried to characterize the co-twin methylation divergence in specific genomic regions between ALL-discordant twin pairs. These patterns of dynamic co-twin methylation changes in these discordant ALL samples were generally consistent among MZ and DZ twins, indicating similarities of methylation abnormalities. As a result, 780, 566, 309, 293 and 2110 DMRs were identified, with a similar distribution pattern across different genomic elements among the five twin pairs.Then we annotate whether these DMRs were located in regulatory elements and identification of genes with recurring methylation alterations in a cohort of ALL patients. We collected blood specimens from 4 pairs of MZ twins and 1 pair of DZ twin that are discordant for ALL. At first, the methylation differences across the genome were addressed globally by Circos software. And then tried to characterize the co-twin methylation divergence in specific genomic regions and differentially methylated gene regions (DMRs) were identified between ALL-discordant twin pairs. Then we annotate whether these DMRs were located in regulatory elements and identification of genes with recurring methylation alterations in a cohort of ALL patients.

Dataset Information

Epigenomic mapping reveals distinct B cell acute lymphoblastic leukemia chromatin architectures and regulators.

Publications

Epigenomic mapping reveals distinct B cell acute lymphoblastic leukemia chromatin architectures and regulators.

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