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Single-cell analysis of accessible chromatin in human mammary epithelial cells using scATAC-seq [scATAC-seq]

ABSTRACT: Epigenome delineates lineage-specific transcriptional programs and restricts cell plasticity to prevent non-physiological cell fate transitions. Although cell diversification fosters tumor evolution and therapy resistance, upstream mechanisms that regulate the stability and plasticity of cancer epigenome remain elusive. Here, we show that 2-hydroxyglutarate (2HG) not only suppresses DNA repair but also mediates high-plasticity chromatin landscape. A combination of single-cell epigenomic and multi-omic approaches demonstrates that 2HG disarranges otherwise well-preserved stable nucleosome positioning and promotes cell-to-cell variability. 2HG induces loss of motif accessibility to luminal-defining transcriptional factors FOXA1, FOXP1 and GATA3 and a shift from luminal to basal-like gene expression. Breast tumors with high 2HG exhibit enhanced heterogeneity with undifferentiated epigenomic signatures linked to adverse patient prognosis. Further, ascorbate-2-phosphate (A2P) eradicates heterogeneity and impairs growth of high 2HG-producing breast cancer cells. These findings suggest 2HG as a key determinant of cancer plasticity and provide a rational strategy to counteract tumor cell evolution.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135412 | GEO | 2020/11/09

REPOSITORIES: GEO

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Transcriptome analysis using RNA-seq in human mammary epithelial cells

Project description:Epigenome delineates lineage-specific transcriptional programs and restricts cell plasticity to prevent non-physiological cell fate transitions. Although cell diversification fosters tumor evolution and therapy resistance, upstream mechanisms that regulate the stability and plasticity of cancer epigenome remain elusive. Here, we show that 2-hydroxyglutarate (2HG) not only suppresses DNA repair but also mediates high-plasticity chromatin landscape. A combination of single-cell epigenomic and multi-omic approaches demonstrates that 2HG disarranges otherwise well-preserved stable nucleosome positioning and promotes cell-to-cell variability. 2HG induces loss of motif accessibility to luminal-defining transcriptional factors FOXA1, FOXP1 and GATA3 and a shift from luminal to basal-like gene expression. Breast tumors with high 2HG exhibit enhanced heterogeneity with undifferentiated epigenomic signatures linked to adverse patient prognosis. Further, ascorbate-2-phosphate (A2P) eradicates heterogeneity and impairs growth of high 2HG-producing breast cancer cells. These findings suggest 2HG as a key determinant of cancer plasticity and provide a rational strategy to counteract tumor cell evolution.

2021-12-17 | GSE161627 | GEO

Single-cell epigenomic variability reveals functional cancer heterogeneity

Project description:Background: Cell-to-cell heterogeneity is a major driver of cancer evolution, progression, and emergence of drug resistance. Epigenomic variation at the single-cell level can rapidly create cancer heterogeneity, but is difficult to detect and assess functionally. Results: We develop a strategy to bridge the gap between measurement and function in single-cell epigenomics. Using single-cell chromatin accessibility and RNA-seq data in K562 leukemic cells, we identify the cell surface marker CD24 as co-varying with chromatin accessibility changes linked to GATA transcription factors in single cells. Fluorescence-activated cell sorting of CD24 high vs. low cells prospectively isolated GATA1 and GATA2 high vs. low cells. GATA high vs. low cells express differential gene regulatory networks, differential sensitivity to the drug imatinib mesylate, and differential self-renewal capacity. Lineage tracing experiments show that GATA/CD24hi cells have the capability to rapidly reconstitute the heterogeneity within the entire starting population, suggesting that GATA expression levels drive a phenotypically relevant source of epigenomic plasticity. Conclusion: Single-cell chromatin accessibility can guide prospective characterization of cancer heterogeneity. Epigenomic subpopulations in cancer impact drug sensitivity and the clonal dynamics of cancer evolution.

2016-12-12 | GSE76224 | GEO

KDM6A Epigenetically Regulates Subtype Plasticity in Small Cell Lung Cancer (scatac)

Project description:Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1,POU2F3, and Inflammatory. Initially SCLC subtypes were thought to be mutually exclusive, butrecent evidence shows intra-tumoral subtype heterogeneity and plasticity between subtypes.Using a CRISPR-based autochthonous SCLC GEMM to study the consequences of KDM6A/UTXinactivation, we found that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1resulting in SCLC tumors with open chromatin at the NEUROD1 promoter that express bothASCL1 and NEUROD1. Mechanistically, KDM6A binds and maintains ASCL1 target genes in anactive chromatin state with its loss increasing H3K27me3 near their promoters leading to a cell state that is primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as \an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides a novel autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.

2023-06-08 | GSE215828 | GEO

High-throughput single-cell mitochondrial DNA genotyping reveals properties of clonal variation in human contexts [CLL-scATAC]

Project description:Natural mitochondrial DNA (mtDNA) sequence variation plays a fundamental role in human disease and enables the clonal tracing of native human cells. While various genotyping approaches revealed mutational heterogeneity in human tissues and single cells, current methodologies are limited by scale. Here, we introduce a high-throughput, droplet-based mitochondrial single-cell Assay for Transposase Accessible Chromatin with sequencing (mtscATAC-seq) protocol and computational framework that facilitate high-confidence mtDNA mutation calling in thousands of single cells. Further, the concomitant high-quality accessible chromatin readout enables the paired inference of individual cell mtDNA heteroplasmy, clonal lineage, cell state, and accessible chromatin regulatory features. Our multi-omic analyses reveals single-cell variation in heteroplasmy of a pathologic mtDNA variant (m.8344A>G), which we tie to intra-individual chromatin variability and clonal evolution. Further, using somatic mtDNA mutations, we clonally trace thousands of hematopoietic cells in vitro and in patients with chronic lymphocytic leukemia, linking epigenomic variability to subclonal evolution in vivo.

2020-07-13 | GSE142743 | GEO

Lineage plasticity enables low-ER luminal tumors to evolve and gain basal-like traits

Project description:Breast tumors expressing lower levels of Estrogen Receptor (ER) represent a distinct subset of breast cancer characterized by the emergence of basal-like characteristics within tumors that are traditionally considered luminal-like. Lineage tracing of these low-ER tumors in the MMTV-PyMT mouse mammary tumor model revealed that the basal-like tumor cells within these tumors arose from normal luminal epithelial cells, suggesting that luminal-to-basal plasticity is responsible for the evolution and emergence of basal-like characteristics within these tumors. This study aims to identify the potential drivers of this plasticity by using single-cell RNA sequencing to identify populations of lineage-restricted luminal cells and luminal-derived basal cells within the tumor, and comparing their gene expression profiles.

2023-03-01 | GSE214815 | GEO

High-throughput single-cell mitochondrial DNA genotyping reveals properties of clonal variation in human contexts [CD34-PBMC-invivo-scATAC]

2020-07-13 | GSE148508 | GEO

Somatic cell fusions reveal extensive heterogeneity in basal-like breast cancer [ChIP-Seq 2]

Project description:Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and it is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells is sufficient to induce luminal-to-basal phenotypic switch implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells. Examination of histone H3K27me3 modifications in various breast cancer cell lines.

2015-06-10 | E-GEOD-38789 | biostudies-arrayexpress

Somatic cell fusions reveal extensive heterogeneity in basal-like breast cancer [RNA-Seq]

2015-06-10 | E-GEOD-69114 | biostudies-arrayexpress

Somatic cell fusions reveal extensive heterogeneity in basal-like breast cancer [ChIP-Seq 3]

Project description:Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and it is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells is sufficient to induce luminal-to-basal phenotypic switch implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells. Examination of histone H3K27Ac modifications in various breast cancer cell lines.

2015-06-10 | E-GEOD-69112 | biostudies-arrayexpress

Somatic cell fusions reveal extensive heterogeneity in basal-like breast cancer [methylation450]

Project description:Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and it is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells is sufficient to induce luminal-to-basal phenotypic switch implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells. Bisulphite converted DNA from 20 breast cancer cell lines were hybridized to the Illumina Infinium HumanMethylation450 BeadChip.

2015-06-10 | E-GEOD-67619 | biostudies-arrayexpress

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