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Published on: January 26, 2018
Histone H3 proline 16 hydroxylation regulates mammalian gene expression
Xijuan Liu1, Jun Wang1,2, Joshua A Boyer1,2
1Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Abstract:
Histone post-translational modifications (PTMs) are important for regulating various DNA-templated processes. Here, we report the existence of a histone PTM in mammalian cells, namely histone H3 with hydroxylation of proline at residue 16 (H3P16oh), which is catalyzed by the proline hydroxylase EGLN2. We show that H3P16oh enhances direct binding of KDM5A to its substrate, histone H3 with trimethylation at the fourth lysine residue (H3K4me3), resulting in enhanced chromatin recruitment of KDM5A and a corresponding decrease of H3K4me3 at target genes. Genome- and transcriptome-wide analyses show that the EGLN2-KDM5A axis regulates target gene expression in mammalian cells. Specifically, our data demonstrate repression of the WNT pathway negative regulator DKK1 through the EGLN2-H3P16oh-KDM5A pathway to promote WNT/β-catenin signaling in triple-negative breast cancer (TNBC). This study characterizes a regulatory mark in the histone code and reveals a role for H3P16oh in regulating mammalian gene expression.
Insights
Researchers discovered a new histone modification, H3P16oh, that impacts gene expression. This finding reveals how histone PTMs regulate cellular processes and offers insights into triple-negative breast cancer.
Area of Science:
- Epigenetics and Molecular Biology
- Cancer Research
- Gene Regulation
Background:
- Histone post-translational modifications (PTMs) are crucial regulators of DNA-templated processes.
- Understanding novel histone modifications is key to deciphering gene regulation mechanisms.
Purpose of the Study:
- To identify and characterize a novel histone PTM in mammalian cells.
- To elucidate the role of this new modification in gene expression and its potential implications in cancer.
Main Methods:
- Mass spectrometry to identify histone modifications.
- Biochemical assays to study protein-histone interactions.
- Genome-wide and transcriptome-wide analyses (ChIP-seq, RNA-seq).
- Cellular and molecular biology techniques to investigate pathway regulation.
Main Results:
- Identification of histone H3 with hydroxylation of proline at residue 16 (H3P16oh), catalyzed by EGLN2.
- H3P16oh enhances the binding of KDM5A to H3K4me3, increasing KDM5A chromatin recruitment and decreasing H3K4me3 levels.
- The EGLN2-H3P16oh-KDM5A axis regulates gene expression, including repression of DKK1 to promote WNT/β-catenin signaling in triple-negative breast cancer (TNBC).
Conclusions:
- Characterization of H3P16oh as a novel regulatory mark in the histone code.
- The EGLN2-H3P16oh-KDM5A pathway plays a significant role in mammalian gene expression.
- This pathway is implicated in the regulation of WNT signaling in triple-negative breast cancer, offering potential therapeutic targets.
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