DPPA2 and DPPA4 as Chromatin Priming Factors (Melanie Eckersley-Maslin)

In this episode of the Epigenetics Podcast, we talked with Melanie Eckersley-Maslin from the Peter McCallum Cancer Center about her work on DPPA2 and DPPA4 as Chromatin Priming Factors.

During her PhD in David Spector’s lab at Cold Spring Harbor Laboratory, Eckersley-Maslin studied monoallelic expression of autosomal genes. She developed an allele-specific RNA-sequencing screen to identify genes expressed differently from their two copies, then examined nuclear positioning, chromatin marks and DNA methylation. The work revealed associations between expression and chromatin state, but did not establish which changes caused the other.

For her postdoctoral work in Wolf Reik’s lab in the UK, she investigated epigenetic regulation of zygotic genome activation, when an embryo begins transcribing its own genome. Using mouse embryonic stem cells that can enter a two-cell-like state, her research identified DPPA2 and DPPA4 as regulators of MERVL- and Zscan4-associated transcription. This work led her to consider how early-acting proteins may prime chromatin for later cell-fate decisions, even when their loss causes effects only much later in development.

Then, Eckersley-Maslin discusses the importance of allowing researchers time to read, think and develop questions, as well as recognizing when to pause projects that are not progressing. She also describes moving from developmental biology into cancer research, bringing questions about cell identity and epigenetic regulation to a cancer-focused research environment.

Her lab now studies DPPA2 and DPPA4 in cancer, including non-small-cell lung cancer. In that context, the proteins associate with chromatin domains marked by H3K4 trimethylation and H2AK119 ubiquitination, rather than the canonical bivalent combination studied in embryos. The function of these domains, including why they lack H3K27 trimethylation despite PRC2 recruitment, remains under investigation. She describes DPPA proteins as possible scaffolds that help recruit or coordinate chromatin machinery, rather than enzymes themselves.

The conversation also covers sequential ChIP, which the lab refined to study the co-occurrence of histone modifications with limited cell numbers. Eckersley-Maslin notes that newer single-cell co-profiling methods may offer greater resolution. Looking ahead, her lab aims to identify other epigenetic priming factors and understand how chromatin states are established at particular genomic regions in particular cell types.

References

• Eckersley-Maslin MA, Thybert D, Bergmann JH, Marioni JC, Flicek P, Spector DL. Random monoallelic gene expression increases upon embryonic stem cell differentiation. Dev Cell. 2014 Feb 24;28(4):351-65. doi: 10.1016/j.devcel.2014.01.017. PMID: 24576421; PMCID: PMC3955261.
• Eckersley-Maslin MA, Svensson V, Krueger C, Stubbs TM, Giehr P, Krueger F, Miragaia RJ, Kyriakopoulos C, Berrens RV, Milagre I, Walter J, Teichmann SA, Reik W. MERVL/Zscan4 Network Activation Results in Transient Genome-wide DNA Demethylation of mESCs. Cell Rep. 2016 Sep 27;17(1):179-192. doi: 10.1016/j.celrep.2016.08.087. PMID: 27681430; PMCID: PMC5055476.

Related Episodes

• The Role of lncRNAs in Tumor Growth and Treatment (Sarah Diermeier)
• The Discovery of Genomic Imprinting (Azim Surani)
• Epigenetic Reprogramming During Mammalian Development (Wolf Reik)

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