Abstract
Many of the cells in our bodies are quiescent, that is, temporarily not dividing. Under certain physiological conditions such as during tissue repair and maintenance, quiescent cells receive the appropriate stimulus and are induced to enter the cell cycle. The ability of cells to successfully transition into and out of a quiescent state is crucial for many biological processes including wound healing, stem cell maintenance, and immunological responses. Across species and tissues, transcriptional, epigenetic, and chromosomal changes associated with the transition between proliferation and quiescence have been analyzed, and some consistent changes associated with quiescence have been identified. Histone modifications have been shown to play a role in chromatin packing and accessibility, nucleosome mobility, gene expression, and chromosome arrangement. In this review, we critically evaluate the role of different histone marks in these processes during quiescence entry and exit. We consider different model systems for quiescence, each of the most frequently monitored candidate histone marks, and the role of their writers, erasers and readers. We highlight data that support these marks contributing to the changes observed with quiescence. We specifically ask whether there is a quiescence histone “code,” a mechanism whereby the language encoded by specific combinations of histone marks is read and relayed downstream to modulate cell state and function. We conclude by highlighting emerging technologies that can be applied to gain greater insight into the role of a histone code for quiescence.
Highlights
Many of the cells in our bodies are quiescent, that is, temporarily not dividing
Does a histone code exist for quiescence? Are there specific patterns of histone tail post translational modifications (PTMs) that dictate or are associated with entry, exit, maintenance, or depth of a quiescent state? If so, do these histone PTMs modulate the physical properties of the DNA? Do these histone marks directly alter the chromatin accessibility of gene promoters and enhancers to induce molecular and phenotypic changes with quiescence? Alternatively, do these histone PTMs serve as binding sites for readers that recognize the PTMs and effect cellular changes during quiescence? If the histone marks serve as recognition sites, what are the most important effectors and what aspects of quiescence do they control? In this review, we address these questions and compare the findings from multiple experimental models of quiescence (Table 1)
2017 Joh et al, 2016 Lee et al, 2016 Lee et al, 2016 Cheedipudi et al, 2015 Lee et al, 2016 Zhou et al, 2018 Zhou et al, 2018 Khoa et al, 2020 Boonsanay et al, 2016 Evertts et al, 2013a Evertts et al, 2013a in quiescent cells and the genes that are repressed by Clr4 in quiescence based on RNA-seq analysis of wild-type and clr4deleted yeast strains (Joh et al, 2016). This disconnect between the two genesets shows that additional studies will be needed to clearly determine whether H3K9 methylation plays a role in regulating transcription with quiescence, whether transcriptional regulation by H3K9 is crucial for viability in the quiescent state, and whether the effects of H3K9 in conjunction with short RNAs constitute part of a quiescence histone code
Summary
Cells can be distinguished from other types of non-dividing cells such as senescent or terminally differentiated cells by their temporary exit from the cell cycle and high likelihood of proliferating in response to a triggering stimulus (Sang and Coller, 2009; Cheung and Rando, 2013; Terzi et al, 2016). Transcriptional changes with quiescence have been analyzed using cDNA libraries (Schneider et al, 1988; Coppock et al, 1993), microarrays (Venezia et al, 2004; Coller et al, 2006; Suh et al, 2012; Johnson et al, 2017), generation sequencing (van Velthoven et al, 2017; Mitra et al, 2018b; Srivastava et al, 2018), and single-cell RNA sequencing methods (Kalakonda et al, 2008; Coller, 2019a) These studies demonstrated widespread gene expression changes with quiescence, some of which are functionally important for the quiescent state (Suh et al, 2012; Johnson et al, 2017; Lee H.N. et al, 2018; Mitra et al, 2018b). Stationary phase isolation Nitrogen-induced starvation; Glucose deprivation Serum-starvation; Contact-inhibition Mitogen withdrawal; Contact inhibition; Loss of adhesion Serum starvation Isolation from inner cell mass of blastocyst Isolation from fetal liver, bone marrow, cord blood Isolation from ventricular-subventricular zone of brain Isolation from muscle of 2 month-old mice Methylcellulose culture medium Isolation from back, belly, or scalpskin
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