Figure 1: The germline cycle links successive generations by transmitting genetic and epigenetic information.

Figure 1: The germline cycle links successive generations by transmitting genetic and epigenetic information.

Figure 2: (Left) The first division of a totipotent zygote, which marks the beginning of the germline cycle. (Right) RNA-seq genome tracks showing how retrotransposon activation can influence nearby gene expression in ESC.

Figure 2: (Left) The first division of a totipotent zygote, which marks the beginning of the germline cycle. (Right) RNA-seq genome tracks showing how retrotransposon activation can influence nearby gene expression in ESC. The epigenomic state of retrotransposons is susceptible to epigenetic inheritance.

The Hackett group investigates the role of epigenetic mechanisms in genome regulation and developmental programming, with a focus on intergenerational epigenetic inheritance. We integrate multi-omics, high-throughput (epi)genetic editing, and environmental perturbations to understand gene regulatory responses across scales, from single cells to organism phenotypes.

Previous and current research

Epigenetic systems stabilise gene expression programmes and underpin cell fate decisions during development. Nevertheless, epigenetic memory must be reset between generations in order to reacquire totipotency: the capacity of an early embryo to give rise to all cell types. The zygote and nascent germline therefore undergo a process of genome-wide epigenetic reprogramming, including DNA demethylation and chromatin remodelling, which restores cellular potential. Our recent work has characterised the mechanisms that underpin this global epigenetic resetting, and has also identified specific systems that ensure correct epigenome priming for development (Gretarsson and Hackett, Nat Struct Mol Biol 2020). At the same time, we have found that some epigenetic information escapes reprogramming and is therefore epigenetically inherited by offspring (Hackett et al., Science 2013; Tang et al., Cell 2015). These loci are preferentially associated with human neurological conditions, and suggest one route for non-DNA sequence-based inheritance. Indeed, our ongoing work has shown that by altering the paternal environmental conditions prior to conception, we can influence the phenotype of subsequent offspring independent of their genotype. Specifically, we have found that acute perturbations to the gut microbiome drive a host response in reproductive tissues, which subsequently manifests as increased disease risk in offspring. 

Future projects and goals

We are broadly interested in the regulatory principles that govern epigenetic control of gene expression patterns, and the consequences of inheriting perturbed epigenetic states across generations.

There are three primary strands of research in our group:

  • Mechanisms that mediate the balance between epigenetic resetting and memory.
  • The context-dependent regulatory function of epigenetic modifications in genome control and development.
  • The influence of parental environments on epigenetic inheritance, and the underlying mechanisms.

To achieve this, we make use of mouse models and pluripotent ES cells, as well as a wide range of genetic and molecular tools. This includes state-of-the-art CRISPR genetic screening and epigenetic editing technologies, single-cell multi-omics, live imaging, and developmental biology approaches. We have also established a gnotobiotic facility to enable further studies into host–microbiome interactions.