Republic of Singapore. Discovery that the Trim28 protein is critical to an embryo's survival opens new research avenues to explore the role of epigenetics in embryology.

The Trim28 protein, normally present in the mother's egg, is essential right after fertilization, to preserve certain epigenetic marks (chemical modifications) on a specific set of genes. Tripartite motif-containing 28 (TRIM28) is encoded in humans by the TRIM24 gene.


Expression of these imprinted genes at the appropriate levels ensures proper development of the embryo. If marks on the imprinted genes are not protected, severe and multiple developmental problems occur in the embryo. Previous studies have shown that both nuclear reprogramming as well as imprinting are vital for the survival and later development of the embryo. However, the underlying mechanisms governing the intricate interplay of these two processes during the early embryonic phase have not been clear, until now.

A study in the journal Science opens additional research avenues to explore the role that epigenetics plays in infertility which in turn could affect other studies in the broader field of embryology. Immediately after fertilization, the majority of the epigenetic marks on the DNA from the sperm and egg cells are erased. The erasure process, termed nuclear reprogramming, allows the genes from the parents to be reset so that the early embryonic cells can develop into any cell types of the body.

On the other hand, certain epigenetic marks on a particular set of genes, some from the mother and some from the father must be preserved. These genes are said to be imprinted by their parent of origin and preservation of these marks is critical for the survival of the newly formed embryo. Expression of these imprinted genes at the appropriate levels ensures proper development of the embryo. If the epigenetic marks on the imprinted genes are not protected, severe and multiple developmental defects occur in the embryo.

Using genetically identical mice from an inbred mouse strain, Drs. Davor Solter and Barbara Knowles, Senior Principal Investigators at the A*STAR Institute of Medical Biology (IMB), observed that none of the embryos resulting from the fertilization of eggs lacking Trim28 survived. The embryos died at varying stages of development, and had very different developmental defects. Every mouse from an inbred strain is genetically identical (i.e. a twin) to every other mouse of the same strain. Given that most genetic diseases attributed to the lack of a single gene have consistently similar defects in every affected individual, the highly varied abnormalities observed in the maternal Trim28-deficient, yet genetically identical mice, were peculiar.

To elucidate these findings and the role of the Trim28 protein during nuclear reprogramming, Dr. Daniel Messerschmidt, the first author of this paper, collaborated with Dr. Anne Ferguson-Smith, a visiting Professor at the A*STAR Singapore Institute for Clinical Sciences (SICS), from the University of Cambridge (UK).

Together, they conducted a comprehensive study on the epigenetic state and the level of expression of a group of imprinted genes known to be important for development. Using highly sophisticated microarray analysis and advanced biochemical techniques, they found that not only is the presence of Trim28 protein important during this critical period, but the timing and amount of Trim28 made available to the newly formed embryo greatly impacts the expression of these imprinted genes at later developmental stages.

Genomic imprinting was first described by Dr. Davor Solter at The Wistar Insitute and by Dr. Azim Surani at Cambridge three decades ago. Recently, Dr Solter suggested that the interplay between nuclear reprogramming and genetic imprints could be explained by a simple analogy from school where the teacher writes a long string of formulas on the black board. At the end of the class he marks stretches to be preserved for the next day's lecture (these are the imprinted marks) and asks the cleaning lady to erase the rest (she performs the reprogramming).

According to Solter, "For the longest time, we didn't know why some bits of the formulas escaped erasure. Through this study, the mystery is finally revealed". Scientists now know Trim28 instructs cleanup activites regarding which part of the formulas should be preserved. Dr. Azim Surani (who was not involved in the study) said "This elegant study on Trim28 provides significant mechanistic insights on how maternal factors in eggs ensure faithful epigenetic inheritance that plays a critical role during development. These findings are relevant not only for the widely practised in vitro fertilization of eggs for the treatment of human infertility, but also more generally for highlighting the importance of epigenetic mechanisms in development and disease."

The senior author, Dr. Barbara Knowles, noted that "Lack of Trim28 in their eggs could explain why some women consistently suffer from multiple failed pregnancies where embryos die at different time points, manifesting multiple, different abnormalities."

Prof Birgitte Lane, Executive Director of IMB, said, "Understanding the role of differential epigenetic modifications is important for the study of human diseases and development. This study has unravelled a critical component essential for nuclear reprogramming. The mechanistic insights revealed have far-reaching clinical implications for treatment of diseases with patient-specific cell therapies. This finding demonstrates how discoveries of fundamental research can shed light on biological questions to open new avenues of formulating therapeutic strategies for the benefits of patients."