Figure 1: The germline cycle resets cellular potential and links successive generations. This is partly enabled by global epigenetic reprogramming events (green text), which erase cellular memory.
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 aims to understand the interplay between epigenetics, genome regulation and cell identity, with emphasis on transgenerational epigenetic inheritance.
Previous and current research
Epigenetic systems stabilise gene expression programmes and underpin cell fate decisions during development. The epigenome therefore acts as a stable ‘memory’ of differentiated cell identity. Nevertheless, epigenetic memory must be reset between generations in order to re-acquire totipotency; the capacity of an early embryo to give rise to all cell types. The zygote and nascent germline therefore undergo a process of extensive epigenetic reprogramming, including DNA demethylation and chromatin remodelling, which restores cellular potential. At the same time, we have found that some epigenetic information escapes reprogramming and is therefore epigenetically inherited by offspring. If the balance between reprogramming and inheriting epigenetic states is adversely affected, this may have a significant impact on normal development, ageing and disease; potentially over several generations.
Our focus is therefore on understanding the flow of epigenetic information through the mammalian germline cycle (Figure 1), which can be considered as the enduring link between successive generations. The germline cycle is a series of fate transitions that gives rise to primordial germ cells (PGC) and ultimately to gametes, which fuse to restart the process. Our studies are linked by aiming to gain a better understanding of the germline cycle and the dramatic epigenetic events which characterise it.
Future projects and goals
We are broadly interested in the regulatory principles that govern epigenetic reprogramming, and the consequences of inheriting perturbed epigenetic states over successive generations. At the molecular level, we investigate the link between epigenetics, retrotransposon regulation, and the emergent transcriptome.
There are three primary strands of research in the lab:
- Mechanisms that mediate the balance between epigenetic reprogramming and inheritance;
- The phenotypic and disease-related consequences of inheriting perturbed epigenetic states;
- The roles and regulation of retrotransposons during the germline cycle.
To achieve this, we make use of a wide range of genetic and molecular tools, as well as mouse models and pluripotent ES cells. This includes state-of-the-art CRISPR/Cas9 genetic screening and epigenetic editing technologies, coupled with genomics, live imaging and developmental biology approaches.