Heard's work over the next decade provided several important conceptual advances in the field of X inactivation and epigenetics in general, thanks to her analysis of nuclear organization and epigenetic changes during early mammalian development. Her group's major discoveries include the remarkable dynamics of epigenetic changes on the X chromosome in early mouse embryos (Okamoto et al., 2004; Patrat et al, 2009); the demonstration that the imprinted form of paternal X inactivation found in mice can occur de novo, and independently of meiotic inactivation in the male germ line (Okamoto et al., 2005); and the more recent discovery of major differences in the nature and timing of events underlying the initiation of X inactivation between species such as mice, rabbits and humans (Okamoto et al, 2011). This work demonstrated the degree to which epigenetic processes such as X inactivation can be adapted to the developmental requirements and constraints in different mammals.
Her lab has also provided several major insights into the role of nuclear organization in X inactivation. They demonstrated that an early function of the non-coding Xist RNA, that triggers the X-inactivation process, is to create a silent nuclear compartment into which genes are recruited (Chaumeil et al., 2006). Soon after they uncovered that certain repetitive elements, long thought of as "junk" DNA, such as LINEs, may play an important role in this nuclear compartmentalization and in chromosome-wide silencing (Chow et al, 2010). Her group also discovered that the X chromosomes undergo transient homologous associations, at a particular stage of the cell cycle and differentiation, and that this helps to coordinate the random monoallelic regulation of the Xist locus and the X-inactivation process (Bacher et al., 2006; Augui et al., 2007; Masui et al, 2011). This was one of the first examples of homologous chromosome interactions during early mammalian development and has opened up the way to explore whether other parts of the mammalian genome undergo similar transient pairing events and if so, whether these participate in establishing random monoallelic expression and epigenetic regulation. Following these findings, she was awarded an ERC Advanced Investigator grant to explore the genome-wide prevalence of random monoallelic expression and chromosome pairing events in more depth.
The most recent studies of Heard and her colleagues on the X-inactivation centre, using technologies that enable the conformation of chromosomes to be explored at the molecular level with high resolution, have revealed a new level of chromosome architecture involving sub-megabase scale domains of preferential interactions (Nora et al, 2012). This work has profound implications not only for the regulatory landscape of the X-inactivation centre, but also for our understanding of genomic and epigenomic organization in general. The discovery of these chromosomal domains allows the prediction of long-range regulatory elements of disease loci, as well as the developmental coordination of gene expression patterns.
In addition to her work on fundamental aspects of epigenetics, Heard has been actively involved in the investigation of epigenetic abnormalities during cancer. She has established close collaborations with the Hospital of the Institut Curie, to investigate the role that epigenetic changes might play in breast cancer (Vincent-Salomon et al, 2007) and with a view to providing prognostic and diagnostic biomarkers, as well as therapeutic strategies using "epidrugs" that can reverse epigenetic aberrations. Combining their expertise in X inactivation and developmental epigenetics, the Heard group is hoping to gain a deeper understanding of epigenetic deregulation in cancer, and its links with genetic mutation.