Transcription coordinates histone amounts and genome content

Abstract

Biochemical reactions typically depend on the concentrations of the molecules involved, and cell survival therefore critically depends on the concentration of proteins. To maintain constant protein concentrations during cell growth, global mRNA and protein synthesis rates are tightly linked to cell volume. While such regulation is appropriate for most proteins, certain cellular structures do not scale with cell volume. The most striking example of this is the genomic DNA, which doubles during the cell cycle and increases with ploidy, but is independent of cell volume. Here, we show that the amount of histone proteins is coupled to the DNA content, even though mRNA and protein synthesis globally increase with cell volume. As a consequence, and in contrast to the global trend, histone concentrations decrease with cell volume but increase with ploidy. We find that this distinct coordination of histone homeostasis and genome content is already achieved at the transcript level, and is an intrinsic property of histone promoters that does not require direct feedback mechanisms. Mathematical modeling and histone promoter truncations reveal a simple and generalizable mechanism to control the cell volume- and ploidy-dependence of a given gene through the balance of the initiation and elongation rates.

Usage of the H3 variants during the S-phase of the cell cycle in Physarum polycephalum

“…Furthermore, the analyses of DNA replication when H3 paralogs are knocked-down failed to reveal significant effect on the incorporation of a Thymidine analog (EdU) ( Supplementary Figure S3 ). Interestingly, these results are consistent with recent studies in yeast, wherein it is shown that the homeostasis of histone concentration and DNA content within the cell is achieved at the transcriptional level ( 36 ). MNase digestion patterns of chromatin showed that the knocking-down H3.3 or H3.1 effected the DNA accessibility (Figure 1D , Supplementary Figure S4 ).…”

“…In contrast, mRNA and de novo deposition of H3.1 are minimal in early S-phase. Therefore, the correlation between the amounts of mRNAs and the amounts of exogenous histones de novo deposited into chromatin showed that the synthesis and the utilization of the two variants of H3 are tightly regulated during the S-phase and suggested that the amounts of H3 paralogs through genome replication are coordinated at the transcription level as shown in yeast ( 36 ). To verify the link between the novo deposition of H3 variants and the amounts of mRNAs the ratios of H3.3 to H3 proteins and mRNAs were calculated (Figure 3F ).…”

“…These results were consistent with the microscopic observations, and suggested a preferential de novo deposition of canonical H3.1 during the S-phase. It has been shown in yeast that the histone protein concentration was coordinated by the amount of transcripts ( 36 ). Hence, to verify whether such coordination was also validated in Physarum, quantification of mRNAs encoding for H3.3 and H3.1, respectively, were carried out (Figure 2E ).…”

“…Recently, it has been shown in budding yeast that the amount of histone proteins is coupled to the DNA content indicating the existence of a coordination that is achieved at the transcription level ( 36 ). The experiments of knock-down of H3 paralogs in Physarum showed that DNA replication is not impaired, but transcription of histone genes revealed a mechanism of mutual compensation of the targeted variant by the untargeted one (Figure 1C ).…”

Mitotic drive in asymmetric epigenetic inheritance

“…Canonical histones are mainly transcribed and translated endogenously during S phase [ 62 , 63 ]. In principle, both old histones and new histones are present at the replication fork.…”