Chaperoning Histone Inheritance
One of the great mysteries of epigenetics is how histones, the eponymous beads on a DNA string, are divided onto newly synthesized DNA strands during cell division. Histones carry modifications that serve as important signals in determining gene expression, regulating developmental programs, and their alteration can even mark disease states . During cell division, DNA is replicated to be packaged into a new cell, and so must its associated histones. In two breakthrough studies published last week in Science, Yu et al and Petryk et al show that parental histones are distributed mostly symmetrically between the newly synthesized leading and lagging DNA strands through tight regulation by histone chaperones.
Working in budding yeast, Yu et al used the eSPAN (enrichment and sequencing of protein-associated nascent DNA) method to look for histone marks that were enriched on either the leading or lagging strand over the entire genome. They used H3K4me3 as a mark for histones from the parental DNA and H3K56ac as a mark for newly synthesized histones. When they compared the ratio of H3K56ac to H3K4me3 marks on sequence reads from the leading strand and the lagging strand, they found that the parental histone marks were mostly evenly distributed between the strands, but there was a slight enrichment of these H3K4me3 marks on the lagging strand. They saw a similar small bias of new histone marks (H3K56ac) on the leading strand. Interestingly, when they made a mutation in either of the genes DPB3 or DPB4 – two non-essential subunits of Pol ɛ, the leading strand DNA polymerase – the bias was significantly enhanced: considerably less of the parental H3H4me3 mark was transferred to the leading strand. Their results suggest that DPB3 and DPB4 assist in the transfer of parental histones onto the leading strand during DNA replication in budding yeast and thus ensure their proper distribution.
To address this same question in mouse embryonic stem cells, Petryk et al developed a new method called SCAR-seq (sister chromatids after replication by DNA sequencing) to track the distribution of parental and new histones on a genome-wide scale. They used H4K20me2 marks as a readout for parental histones and H4K5ac marks for newly synthesized histones. They found that the parental H4K20me2 marks were distributed evenly between the leading an lagging strands for the most part, but had a slight bias toward the leading strand, which is the opposite result seen in budding yeast in Yu et al, indicating differences between the two biological systems. H4K5ac marks were also evenly distributed between leading and lagging strands, but showed a slight lagging strand bias. When Petryk et al mutated the histone-binding domain of the replicative helicase MCM2 so that it could no longer bind histones, they saw a strong bias in distribution of parental histone marks to the leading strand, exacerbating the bias that was seen in normal cells. Thus MCM2 is required for distributing parental histones to the lagging strand during DNA replication.
Both of these studies deepen our understanding of how epigenetic information is transferred to the next generation. Chaperones such as DPB3/DPB4 and MCM2 tightly regulate the symmetric distribution of parental histones to both the leading and lagging DNA strands, securing their inheritance. The use of these different chaperone proteins may be a method that cells use to determine different epigenetic states in future generations and thus may be important for enacting new developmental programs.
Yu C*, Gan H*, Serra-Cardona A, Zhang L, Gan S, Sharma S, Johansson E, Chabes A, Xu R, and Zhang Z (2018). A mechanism for preventing asymmetric histone segregation onto replicating DNA strands. Science, 361 (6409):1386-1389. DOI: 10.1126/science.aat8849. *co-first authors
Petryk N*, Dalby M*, Wenger A, Stromme CB, Strandsby A, Andersson R, and Groth A (2018). MCM2 promotes symmetric inheritance of modified histones during DNA replication. Science, 361 (6409) 1389-1392. DOI: 10.1126/science.aau0294. *co-first authors