Biology subjects

Eaves, C. J.

Publications and source records attributed to Eaves, C. J..

6 recordsLinked to original sources

bioRxiv2025

Cell type-specific epigenomic variation and its association with genotype in the human breast

BackgroundUnderstanding the interplay between genomic variation and the epigenome is fundamental to the study of development and mechanisms of disease. Previous studies have leveraged population-scale genotype surveys to associate alleles with epigenomic states in heterogenous tissue types. However, epigenomes are inherently cell type-specific, giving rise to unique genome-epigenome interactions that can influence distinct functional states and susceptibility to disease. Moreover, the extent of individual variation in cell type-specific epigenotypes remains poorly understood, posing additional challenges to accurately link genotypes with epigenomic features. ResultsWe generated comprehensive genomic and epigenomic profiles of four functionally defined human breast epithelial cell types from eight healthy individuals. To quantify inter-individual epigenomic variation, we developed a statistical framework that measures variability in histone modification landscapes across individuals. This analysis revealed substantially greater variation in repressive chromatin marked by H3K27me3 than in active chromatin marked by H3K27ac and H3K4me3. Integrative chromatin state analysis further identified enhancer elements as the principal source of epigenomic divergence between individuals. Stable enhancer states corresponded to high-confidence cis-regulatory elements that underpin cell type-specific transcriptional programs, whereas variable enhancer states were enriched for environmentally responsive regulatory circuits. Mapping genetic variants associated with chromatin state variation uncovered extensive cell type-specificity, with nearly 90% of regulatory variants detected in only a single cell type. These associations were strongly enriched within active regulatory chromatin and, when integrated with gene expression, enabled the prioritization of functional regulatory variants. We experimentally validated one such variant, rs75071948, demonstrating allele-specific regulation of ANXA1 expression using CRISPR/Cas9 genome editing. ConclusionsOur study defines the landscape of normal epigenomic variation across the major human breast epithelial cell types and demonstrates that genome-epigenome interactions are highly cell type-specific. These findings establish cell type as a critical determinant of the functional interpretation of regulatory genetic variation and provide a framework for understanding how inherited genetic variation shapes normal breast biology and disease susceptibility.

genomics↗

bioRxiv2024

Human lymphoid-neutrophil/monocyte restriction co-ordinately activates increased proliferation despite parallel heterogeneity in transcriptional changes

Recent studies indicate the human lympho-myeloid restriction process to be a different and more heterogeneous one than historically inferred. Here we describe the development of bulk and clonal culture systems that efficiently support early B-lymphoid differentiation and their use to identify biological and molecular changes that accompany their initial restriction from subsets of CD34+ human cord blood cells with lympho-myeloid-limited potential. Analyses of the changes observed revealed the acquisition of B-lymphoid- and neutrophil/monocyte (NM)-restricted properties are accompanied by a concomitantly accelerated and lineage-shared cell cycling activity and loss of self-renewal properties. Parallel, single-cell transcriptome analysis identified reduced expression of multiple self-renewal-associated genes and an accompanying heterogeneous activation of lineage-regulatory modules during the production of B, NM and dendritic cell precursors. These results uncover a connected regulation of lineage-shared proliferation control with persistent heterogeneity in the biological and transcriptional changes in the same cells undergoing B and NM lineage restriction.

immunology↗

bioRxiv2020

A JAK/STAT-Mediated Inflammatory Signaling Cascade Drives Oncogenesis In AF10-Rearranged AML

Leukemias bearing fusions of the AF10/MLLT10 gene are associated with poor prognosis, and therapies targeting these fusion proteins are lacking. To understand mechanisms underlying AF10 fusion-mediated leukemogenesis, we generated inducible mouse models of AML driven by the most common AF10 fusion proteins, PICALM/CALM-AF10 and KMT2A/MLL-AF10, and performed comprehensive characterization of the disease using transcriptomic, epigenomic, proteomic, and functional genomic approaches. Our studies provide a comprehensive map of gene networks and protein interactors associated with key AF10 fusions involved in leukemia. Specifically, we report that AF10 fusions activate a cascade of JAK/STAT-mediated inflammatory signaling through direct recruitment of JAK1 kinase. Inhibition of the JAK/STAT signaling by genetic Jak1 deletion or through pharmacological JAK/STAT inhibition elicited potent anti-oncogenic effects in mouse and human models of AF10 fusion AML. Collectively, our study identifies JAK1 as a tractable therapeutic target in AF10-rearranged leukemias. STATEMENT OF SIGNIFICANCEGene fusions of AF10/MLLT10 are recurrent in acute myeloid and lymphoid leukemia and are associated with extremely poor survival outcomes. We show that the JAK1 kinase is required for activation of the AF10 fusion oncotranscriptome and for leukemogenesis. Since a number of JAK/STAT pathways inhibitors are in clinical development or approved for use, our studies may help develop a therapeutic strategy for AF10-rearranged leukemias.

cancer biology↗

bioRxiv2019

Mammary epithelial cells have lineage-restricted metabolic identities

Cancer metabolism adapts the metabolic network of its tissue-of-origin. However, breast cancer is not a disease of a singular origin. Multiple epithelial populations serve as the culprit cell-of-origin for specific breast cancer subtypes, yet knowledge surrounding the metabolic network of normal mammary epithelial cells is limited. Here, we show that mammary populations have cell type-specific metabolic programs. Primary human breast cell proteomes of basal, luminal progenitor, and mature luminal populations revealed their unique enrichment of metabolic proteins. Luminal progenitors had higher abundance of electron transport chain subunits and capacity for oxidative phosphorylation, whereas basal cells were more glycolytic. Targeting oxidative phosphorylation and glycolysis with inhibitors exposed distinct metabolic vulnerabilities of the mammary lineages. Computational analysis indicated that breast cancer subtypes retain metabolic features of their putative cell-of-origin. Lineage-restricted metabolic identities of normal mammary cells partly explain breast cancer metabolic heterogeneity and rationalize targeting subtype-specific metabolic vulnerabilities to advance breast cancer therapy.

cell biology↗

bioRxiv2019

Variable Retention of Differentiation-specific DNA Replication Timing in Human Pediatric Leukemia

Human B-lineage precursor acute lymphoid leukemias (BCP-ALLs) comprise a group of genetically and clinically distinct disease entities with features of differentiation arrest at known stages of normal B-lineage differentiation. We previously showed BCP-ALL cells display unique and clonally heritable DNA-replication timing (RT) programs; i.e., programs describing the variable order of replication of megabase-scale chromosomal units of DNA in different cell types. To determine the extent to which BCP-ALL RT programs mirror or deviate from specific stages of normal human B-cell differentiation, we transplanted immunodeficient mice with quiescent normal human CD34+ cord blood cells and obtained RT signatures of the regenerating B-lineage populations. We then compared these with RT signatures for leukemic cells from a large cohort of BCP-ALL patients. The results identify BCP-ALL subtype-specific features that resemble specific stages of B-cell differentiation and features that appear associated with relapse. These results suggest the genesis of BCP-ALL involves alterations in RT that reflect clinically relevant leukemia-specific genetic and/or epigenetic changes. SUMMARYGenome-wide DNA replication timing profiles of >100 pediatric leukemic samples and normally differentiating human B-lineage cells isolated from xenografted immunodeficient mice were generated. Comparison of these identified potentially clinically relevant features that both match and deviate from the normal profiles.

cancer biology↗

bioRxiv2018

YB-1 Is Critical For The Genesis And Progression Of KRAS Mutated Human Breast Cancer

Breast cancer heterogeneity has made it challenging to elucidate shared mechanisms that underpin properties that are critical to their growth in vivo. Here, we interrogate the role of YB-1 protein in the in vivo tumorigenic activity of de novo well as cell line models of human breast cancer. Short-hairpin RNA-mediated knockdown of YB-1 in MDA-MB-231 cells blocked both their local tumour-forming and lung-colonizing activity in transplanted immunodeficient mice. YB-1 knockdown also revealed its important role at early stages of human mammary cell transformation in the generation of invasive ductal carcinoma and ductal carcinoma in situ produced in mice transplanted with freshly isolated human mammary cells transduced, respectively, with KRASG12D, or myristoylated-AKT1. Conversely, upregulated expression of YB-1 in the poorly tumorigenic T47D cells enhanced this activity. Mechanistically, reducing YB-1 levels in MDA-MB-231 cells impaired their induction of HIF1, and G3BP1, known YB-1 translational targets and key elements of a stress-adaptive program.

cancer biology↗