Journal
GENES & DEVELOPMENT
Volume 32, Issue 7-8, Pages 497-511Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.311027.117
Keywords
acetyl-CoA; histone acetylation; metabolism; calcium; NFAT1; glioblastoma
Categories
Funding
- Pew Biomedical Scholar Award
- Advancing Graduate Studies (AGS) Patel Family Scholar Award
- Penn-PORT (Penn-Post-doctoral Opportunities in Research and Teaching) Institutional Research and Academic Career Development Award post-doctoral fellowship [K12 GM081259]
- American Diabetes Association post-doctoral fellowship [1-18-PDF-144]
- University of Pennsylvania
- National Institutes of Health [1DP2CA186573-01]
- Pew Charitable Trusts
- National Research Service Award from the National Institutes of Health [T32 GM008515]
- National Science Foundation Graduate Research Fellowship [1451512]
- Pennsylvania Department of Health Commonwealth Universal Research Enhancement Program (CURE) grant
- [R01CA174761]
- [1F31CA189744]
- [F99CA222741]
- [K22ES026235]
- NATIONAL CANCER INSTITUTE [R01CA078831, DP2CA186573, R01CA174761, F99CA222741, F31CA189744] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [K22ES026235] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [K12GM081259, T32GM008515] Funding Source: NIH RePORTER
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The metabolite acetyl-coenzyme A (acetyl-CoA) is the required acetyl donor for lysine acetylation and thereby links metabolism, signaling, and epigenetics. Nutrient availability alters acetyl-CoA levels in cancer cells, correlating with changes in global histone acetylation and gene expression. However, the specific molecular mechanisms through which acetyl-CoA production impacts gene expression and its functional roles in promoting malignant phenotypes are poorly understood. Here, using histone H3 Lys27 acetylation (H3K27ac) ChIP-seq (chromatin immunoprecipitation [ChIP] coupled with next-generation sequencing) with normalization to an exogenous reference genome (ChIP-Rx), we found that changes in acetyl-CoA abundance trigger site-specific regulation of H3K27ac, correlating with gene expression as opposed to uniformly modulating this mark at all genes. Genes involved in integrin signaling and cell adhesion were identified as acetyl-CoA-responsive in glioblastoma cells, and we demonstrate that ATP citrate lyase (ACLY)-dependent acetyl-CoA production promotes cell migration and adhesion to the extracellular matrix. Mechanistically, the transcription factor NFAT1 (nuclear factor of activated T cells 1) was found to mediate acetyl-CoA-dependent gene regulation and cell adhesion. This occurs through modulation of Ca2+ signals, triggering NFAT1 nuclear translocation when acetyl-CoA is abundant. The findings of this study thus establish that acetyl-CoA impacts H3K27ac at specific loci, correlating with gene expression, and that expression of cell adhesion genes are driven by acetyl-CoA in part through activation of Ca2+-NFAT signaling.
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