Epigenetic inheritance: histone bookmarks across generations

Abstract

Multiple circuitries ensure that cells respond correctly to the environmental cues within defined cellular programs. There is increasing evidence suggesting that cellular memory for these adaptive processes can be passed on through cell divisions and generations. However, the mechanisms by which this epigenetic information is transferred remain elusive, largely because it requires that such memory survive through gross chromatin remodeling events during DNA replication, mitosis, meiosis, and developmental reprogramming. Elucidating the processes by which epigenetic information survives and is transmitted is a central challenge in biology. In this review, we consider recent advances in understanding mechanisms of epigenetic inheritance with a focus on histone segregation at the replication fork, and how an epigenetic memory may get passed through the paternal lineage.

Keywords: epigenetic; gamete; histone; inheritance; polycomb; replication.

Figure 1

Histone dynamics and inheritance of epigenetic information at the replication fork, as exemplified by the methylation of histone H3 on lysine 27. De novo nucleosome assembly proceeds through the nuclear import of histone H3-H4 dimers via the ASF1 histone chaperone. Differential thermodynamic affinities towards histones facilitate the transfer of these predominantly unmodified histones to the PCNA-bound CAF-1. The latter facilitates the formation and deposition of stable (H3.1-H4)₂ tetramers to be completed by the addition of two juxtaposed H2A-H2B dimers. Nucleosomes encountering the replication fork are transiently bound and dissociated by the MCM2 subunit of the CMG replicative helicase as well as by the histone chaperone FACT. The exact mechanism by which these multi-PTM decorated histone tetramers segregate onto nascent DNA strands remains to be fully elucidated. Polycomb proteins persist at the replication fork through internucleosomal contacts. Only histone H3 N-terminal tails marked on lysine 27 are shown for simplicity. Histones H3, H4, and H2A-H2B are shown in blue, yellow and grey, respectively. Methyl marks are shown in red. Figure is adapted from [2].

Figure 2

Restoration of repressive H3K9 and H3K27 methylation marks throughout the cell cycle. Replicated nascent DNA strands receive an equal influx of newly synthesized and parental histones effectively diluting pre-existing posttranslational modifications. H3K9me1 increases in S-phase through the deposition of PRDM3/16 and SETDB1-modified histones. A subset of the monomethylated histones are perhaps converted into higher methylation states, however, steady states are achieved though the propagation of the marks onto unmodified histones from the end of replication until the subsequent G₁ phase. Although H3K27me mirrors these cell cycle coupled kinetics, the enzyme responsible for H3K27 monomethylation has yet to be unequivocally identified. Red, green, and yellow dots represent parental methyl marks, and subsequent methylation events on modified and unmodified substrates, respectively.

Figure 3. Survival of a Paternal Epigenetic Memory Across Generations

Propagation of an epigenetic memory across generations in mammals requires its passage from the original epigenetic signaling event to the germline, into the embryo and through development. Potential routes of transmission are shown with the locus of epigenetic inheritance itself depicted by a green box and the forward facing nucleosome. (Top Panel) How the epigenetic stimulus itself arrives in the developing sperm is unclear. While little is known about how the epigenetic memory remains intact through the large-scale nucleosomal restructuring that occurs during the spermatogonia to sperm transition (e.g., testis-specific histone incorporation, transition proteins [Trp] and replacement with protamines [PRM1/2]), there are a number of possibilities. With their ability to mark loci through mitosis, it is possible that bromodomain proteins may mark certain loci through this transition. Perhaps the strongest evidence is for H3K27me3 either alone or together with H3K4me3 that are retained in the mature sperm and may be propagated post-fertilization. The mechanisms involved are largely speculative, but likely involve PRC2 bridging these transitions either alone or in concert with histone chaperones such as HIRA during the dynamic nucleosome turnover throughout spermatogenesis. (Bottom Panel) Faithful transmission to F2 then requires survival through maternally mediated reprogramming events such as the replacement of protamines with maternal H3. Recent evidence suggests that despite this reprogramming, certain marks such as H3K27me3 might be retained from sperm through the 2-cell stage. As in spermatogenesis, it remains unknown but plausible that bromodomains or other readers may similarly mark epigenetic loci. Gametogenesis also poses a threat to the epigenetic memory, however mounting evidence suggest that H3K27me3 and even H3K36me3 can be faithfully propagated throughout gametogenesis perhaps through the methyltransferase NSD1. From gametogenesis, the cycle would then repeat thus allowing propagation to F3 and on until this epigenetic memory is either diluted or otherwise erased.