JMJD1B, a novel player in histone H3 and H4 processing to ensure genome stability

Francisco Saavedra,Camila Rojas-Villalobos,Raquel Quatrini,Zachary A. Gurard-Levin,Alejandra Loyola,Geneviève Almouzni,Isabelle Vassias

doi:10.1186/s13072-020-00331-1

Abstract

BackgroundMaintaining a proper supply of soluble histones throughout the cell cycle is important to ensure chromatin and genome stability. Following their synthesis, histones undergo a series of maturation steps to prepare them for deposition onto chromatin.ResultsHere, we identify the lysine demethylase JMJD1B as a novel player in the maturation cascade that contributes to regulate histone provision. We find that depletion of JMJD1B increases the protein levels of the histone chaperone tNASP leading to an accumulation of newly synthesized histones H3 and H4 at early steps of the histone maturation cascade, which perturbs chromatin assembly. Furthermore, we find a high rate of JMJD1B mutations in cancer patients, and a correlation with genomic instability.ConclusionsOur data support a role for JMJD1B in fine-tuning histone supply to maintain genome integrity, opening novel avenues for cancer therapeutics.

Highlights

Maintaining a proper supply of soluble histones throughout the cell cycle is important to ensure chro‐ matin and genome stability
Cells treated with siJMJD1B accumulate soluble histones H3 and the histone chaperone tNASP Our lab previously described that SetDB1 establishes H3K9me1 during translation [28]
We further characterized SetDB1 interactions by mass spectrometry from cytosolic extracts derived from HeLa cells and, in addition to known players in metabolizing newly synthesized histones, we identified a new interacting partner, the demethylase JMJD1B, a candidate tumor suppressor [10] with H3K9me1/2 and H4R3me2 demethylase activities [2, 16] (Additional file 1: Figure S1)

Summary

Introduction

Maintaining a proper supply of soluble histones throughout the cell cycle is important to ensure chro‐ matin and genome stability. Following their synthesis, histones undergo a series of maturation steps to prepare them for deposition onto chromatin. Histone synthesis is tightly coupled to DNA replication and peaks during the G1/S phase transition to account for doubling the genome. At this time, canonical histone genes are expressed, in contrast to histone variant genes, that are expressed at basal levels throughout the cell cycle [21, 22]. Cells utilize various mechanisms to ensure proper histone provision, including

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Discussion

Conclusion