PT  - JOURNAL ARTICLE
AU  - Meena Kusi
AU  - Maryam Zand
AU  - Chun-Lin Lin
AU  - Chiou-Miin Wang
AU  - Nicholas D. Lucio
AU  - Nameer B. Kirma
AU  - Jianhua Ruan
AU  - Tim H.-M. Huang
AU  - Kohzoh Mitsuya
TI  - Single-cell chromatin profiling reveals demethylation-dependent metabolic vulnerabilities of breast cancer epigenome
AID  - 10.1101/2020.02.18.954495
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.18.954495
4099  - http://biorxiv.org/content/early/2020/02/19/2020.02.18.954495.short
4100  - http://biorxiv.org/content/early/2020/02/19/2020.02.18.954495.full
AB  - Metabolic reprogramming in cancer cells not only sustains bioenergetic and biosynthetic needs but also influences transcriptional programs, yet how chromatin regulatory networks are rewired by altered metabolism remains elusive. Here we investigate genome-scale chromatin remodeling in response to 2-hydroxyglutarate (2HG) oncometabolite using single-cell assay for transposase accessible chromatin with sequencing (scATAC-seq). We find that 2HG enantiomers differentially disrupt exquisite control of epigenome integrity by limiting α-ketoglutarate (αKG)-dependent DNA and histone demethylation, while enhanced cell-to-cell variability in the chromatin regulatory landscape is most evident upon exposure to L2HG enantiomer. Despite the highly heterogeneous responses, 2HG largely recapitulates two prominent hallmarks of the breast cancer epigenome, i.e., global loss of 5-hydroxymethylcytosine (5hmC) and promoter hypermethylation, particularly at tumor suppressor genes involved in DNA damage repair and checkpoint control. Single-cell mass cytometry further demonstrates downregulation of BRCA1, MSH2 and MLH1 in 2HG-responsive subpopulations, along with acute reversal of chromatin remodeling upon withdrawal. Collectively, this study provides a molecular basis for metabolism-epigenome coupling and identifies metabolic vulnerabilities imposed on the breast cancer epigenome.