The “dark” parts of the genome – including transposons, repeats, and long non-coding RNAs – have been recently implicated in regulating the 3D genome architecture and gene expression. However, their role in early developmental transitions remains unclear. In the project supported by the ERC Starting Grant, Joanna Jachowicz will be able to study the role of the dark genome in regulating early mammalian development. Possible applications of this work include a better understanding of reproductive medicine and advances in the field of stem cell research.
Jachowicz’s interest in early mammalian development dates to her undergraduate studies. At that time, she observed that during early development, embryonic cells undergo massive rearrangements of their nuclear architecture, as well as major changes in their transcription patterns. Despite the dynamic reorganization of the nuclei, the embryo seemed to “know” exactly when to carry out each step of development, she says. During Jachowicz’s graduate studies, she became fascinated by the mechanistic aspects of early development and studied the function of the “dark” genome elements in regulating its proper progression. Jachowicz determined that the timely expression patterns of several classes of “dark” genome elements regulated the genome’s spatial architecture in early embryonic cells.
During her postdoctoral studies at Caltech, Jachowicz dived into the mechanisms that the “dark” genome utilizes to regulate genome functions. To better understand the genome-wide role of the “dark” parts, she went on to co-develop a new method for investigating the complex interplay between 3D genome architecture and transcriptome in cell nuclei. This technique, called SPRITE, allowed Jachowicz to simultaneously tag DNA and RNA molecules within the same nucleus, thus generating comprehensive 3D DNA-RNA organization maps.
Now, the ERC Starting Grant will allow the Jachowicz lab to use these technological advances to generate the first spatiotemporal maps of a developing embryo and reveal the simultaneous 3D DNA and RNA organizational patterns throughout early mouse development. Because changes to the 3D genome and transcriptome during these early cell state transitions occur almost simultaneously, mapping their crosstalk at the level of individual cells will allow the establishment of causal relations between nuclear architecture and the transcriptome. Ultimately, the Jachowicz lab aims to identify novel elements in the “dark” genome that lead to the very first cell fate decision.
Despite the seemingly infallible developmental program during mammalian embryogenesis, pregnancies still have a considerable failure rate within the first few days following fertilization. Thus, studying these very early stages of development will permit the design of better tools to advance reproductive medicine.
Furthermore, the Jachowicz lab’s research could have an impact on gene regulation in stem cell research. As the early embryonic cells gradually lose their potency with each new cell fate decision, identifying factors that revert cell fate decisions could prove instrumental in advancing stem cell research. “Receiving an ERC Starting Grant to carry out this research at IMBA, a big name in RNA biology and stem cell research, demonstrates to me the relevance of my questions for the advancement of the fields,” says Joanna Jachowicz.