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Going Green! – How Histone Recycling Promotes the Preservation of Pristine Epigenetic Landscapes

The climate crisis and our need to produce less waste have made recycling an everyday concept; however, whether histone proteins “go green” during DNA replication has remained somewhat in doubt. The epigenetic environment becomes disrupted during DNA replication and must be restored to maintain genome regulation and cell identity; now, two high-efficiency epigenetic studies provide more evidence that histone recycling preserves epigenetic landscapes in a pristine condition. Flury and colleagues propose that a rapid, short-term memory of recycled H2A-H2B modifications facilitates the restoration of stable H3-H4 chromatin states in vitro, while, Mühlen, Li, Dovgusha, and colleagues use mutant Drosophila embryos to show how parental histone recycling supports the restoration of genomic positions in vivo.

Short-term Impact of H2A-H2B Recycling Provides a Long-lasting Effect on Nucleosomal Neighbors

The nucleosome comprises a histone octamer formed of an H3-H4 tetramer and two flanking H2A-H2B dimers that package 146 bp of DNA. While studies have established H3-H4 as a central unit for transferring long-term epigenetic memory during DNA replication via histone recycling, we know less regarding the reuse of H2A-H2B. To explore if H2A-H2B also goes green, an environmentally conscious team led by Anja Groth (University of Copenhagen, Denmark) employed innovative sequencing-based techniques – ChOR-seq and SCAR-seq – to track the occupancy of modified H2A-H2B on replicating DNA in mouse embryonic stem cells. Their entirely sustainable results now show that a rapid, short-term memory mediated by H2A-H2B recycling restores the long-lasting chromatin states of their H3-H4 nucleosomal neighbors.

Let’s hear from Flury and colleagues about how H2A-H2B recycling helps to maintain the epigenetic landscape:

  • Combining the temporal and spatial resolution of ChOR-seq and SCAR-seq with the inhibition of de novo ubiquitination demonstrates the accurate recycling of modified H2A-H2B during DNA replication
    • H2A-H2B recycling maintains H2AK119ub1 Polycomb domain structure, H2A.Z demarcation of transcriptional start sites, and H2BK120ub1 decoration of gene bodiesThis data also supports genome-wide H2A-H2B recycling during euchromatin and heterochromatin replication
    • Therefore, H2A-H2B transmits information regarding chromatin states to newly synthesized DNA, contributing to chromatin restoration and long-term epigenetic memory
  • H2A-H2B becomes symmetrically segregated on daughter strands via the lagging strand polymerase POLA1 during recycling, which functions independently of H3-H4 recycling
  • H2A-H2B becomes rapidly restored post-replication in a timeframe comparable to transcription restart
    • H2A.Z and H2BK120ub1 characterize nascent chromatin prior to transcription restart
    • The rapid restoration kinetics of H2AK119ub1 guides the accurate restoration of H3K27me3 post-replication
  • Therefore, short-term memory of dynamic modifications through H2A-H2B recycling helps to propagate the epigenome and establish slower, long-term memory provided by H3-H4 modifications such as H3K27me3

This resourceful research suggests that the rapid, short-term memory provided by H2A-H2B recycling during DNA replication helps to maintain long-lasting memory based on H3-H4 chromatin states. Future work by these eco-friendly epigeneticists will aim to identify H2A-H2B handlers, dissect the role of H2A-H2B/H3-H4 recycling in homeostasis and differentiation using recycling mutants, and explore the relevance of H2A-H2B recycling to epigenetic inheritance.

Parental Histone Recycling Passes Down an Epigenetic Legacy In Vivo

As human parents pass on words of wisdom to their offspring in the hope that this spoken legacy will serve them in the future (“please recycle and ALWAYS wear clean underwear”), the inheritance of chromatin states during DNA replication requires nucleosomes from parental histones to instruct “newly” synthesized histones with their epigenetic legacy.

A biodegradable bunch of researchers led by Ufuk Günesdogan (University of Göttingen/Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany) explored this concept in their recent in vivo study, which used mutant Drosophila embryos to show how parental histone recycling during DNA replication supports the restoration of genomic positions in vivo. This unfortunate mutant (HisC) carries a chromosomal deletion that includes all histone genes; therefore, nucleosome assembly during DNA replication relies on parental nucleosomes only from cell cycle 14 onward, by which point the maternal pool of histone mRNAs has run dry. Their findings suggest that parental histone recycling helps to pass down an epigenetic legacy to preserve epigenetic landscapes during DNA replication in vivo.

Let’s hear from Mühlen, Li, Dovgusha, and colleagues on the epigenetic legacy afforded by parental histone recycling:

  • Analysis of chromatin reassembly in mutant embryos revealed increased chromatin accessibility, suggesting parental histones become recycled during DNA replication but reassemble at lower occupancy and in a disorganized fashion
    • Parental linker histone H1, which aids the formation of nucleosome arrays and chromatin compaction, undergoes recycling and appropriate deposition during/after DNA replication
  • The lack of adequate global nucleosome re-establishment prompts the upregulated expression of typically inactive genes and the increased expression of genes with low-to-mid-level expression
    • Transcriptional dysregulation involves the premature release of paused RNAPII and subsequent transcriptional elongation and also spurious transcription initiation within gene bodies/intergenic regions
    • Of note, the developmental gene expression program remains under partial control
  • Analysis of the mutant embryo model demonstrates that parental histone recycling allows the restoration of the genomic positions of parental histones during/after DNA replication
    • Modified histones H3 and H2A and H2B exhibit a “positional memory” of their previous location
    • Active and repressive modifications maintain positional information during DNA replication; however, parental histones with active modifications become dispersed within gene bodies, which correlates with spurious transcription

These ecologically faithful findings prove that in vivo parental histone recycling provides an epigenetic legacy in a well-understood model system, constituting a process that preserves epigenetic landscapes in a pristine condition during DNA replication. These data also confirm the findings regarding H2A-H2B recycling highlighted in the previous study and extend the histone recycling process to include the all-important histone H1 linker.

Go Green or Go Home!

These environmentally friendly studies provide robust evidence for parental histone recycling as a crucial component of the DNA replication process, where it maintains the epigenetic landscapes of daughter cells in a pristine condition. The eco-friendly epigenetic message is clear in vitro and in vivo – go green or go home!

For more on histone recycling in embryonic stem cells, see Cell, February 2023, and Drosophila embryos, see Science Advances, February 2023.

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