Award Finalists 2023
Alicia K. Michael, Ph.D.
As a Ph.D. student with Dr. Carrie Partch, Alicia K. Michael showed how the circadian transcription factor (TF), CLOCK-BMAL1, is repressed in healthy and diseased tissues. Although it was long-known that TFs function in chromatin, the only available structures were of TFs bound to isolated DNA duplexes. To understand how TFs recognize their DNA motif within chromatin, during her postdoctoral work in the lab of Dr. Nicolas Thomä, she developed an assay to examine the engagement of a TF with its motif at all positions within a nucleosome, enabling cryo-EM structures of OCT4-SOX2 bound to nucleosomal DNA. In a continued pursuit to unravel the molecular clockwork, Alicia determined the cryo-EM structure of CLOCK-BMAL1 bound to a native nucleosome showing how TF-histone interactions are critical for circadian cycling.
The DNA in our cells is wrapped around histone proteins to form nucleosomes, then further condensed into chromatin, which helps package the DNA in the nucleus and plays a role in the regulation of gene expression. While it has long been known in the field of epigenetics that transcription factors must be able to find and bind to their DNA binding motifs even when ‘hidden’ in chromatin, it was unknown how this was happening or what this looked like. Together with the lab of Dr. Dirk Schübeler, Alicia developed a method to test the binding of TFs throughout the nucleosome, enabling structure determination of OCT4-SOX2 bound to its chromatinized motif. The structures reveal how, by recognizing just part of its DNA-binding motif, only a subset of OCT4’s DNA-binding domains appears to hold the DNA, while SOX2 lifts the DNA away from the surface of the nucleosome. The structures also proved that a partial DNA-binding motif engagement is sufficient for these factors to engage chromatin in vivo. This may indicate how the transcription factors open chromatin and allow the recruitment of additional factors for DNA transcription and subsequent gene expression.
Adel Al Jord, Ph.D.
Of Syrian and Russian origins, Adel Al Jord grew up in Dubai where he attended an American High-School before moving to his now adoptive France for university studies. He trained at the Manga-Orlow laboratory of New York University, before obtaining a PhD in Cell & Developmental Biology with Alice Meunier & Nathalie Spassky at the Ecole Normale Supérieure in Paris. Recently, Adel was an EMBO New Venture Fellow with Lucas Pelkmans at the University of Zurich. He is currently a Collège de France Research Fellow in Paris, working with Marie-Hélène Verlhac & Marie-Emilie Terret at the Center for Interdisciplinary Research in Biology, and will soon transition to a group leader position. Adel’s cross-disciplinary research investigates mechanisms of organelle remodeling in cells that, on an organism scale, sustain health or promote disease.
To function, organisms rely on vital organs which, in turn, rely on specialized cells. At the subcellular scale, cell specialization is notably driven by robust mechanisms of organelle remodeling. Thus, discovering these mechanisms is key for the fundamental understanding of organisms in health and disease, as well as for improved strategies of organ engineering. My research aims to identify these mechanisms in diverse contexts. Our recent work in female germ cells named oocytes explored the remodeling of nuclear RNA-processing organelles, known as condensates. Using an interdisciplinary approach, we found that oocytes deploy a mechanical mechanism, based on cytoskeletal force tuning in the cytoplasm, to agitate the nucleus and functionally remodel condensates in the nucleoplasm. Disrupting this physical dialogue between the cytoplasm and nucleoplasm compromises condensate-associated RNA processing, hindering oocyte divisions that drive female fertility. Beyond reproductive biology, this study ventured into unexplored grounds of mechanobiology, revealing a new function for the cytoskeleton and a new mechanism of condensate mechano-regulation. This grants fresh viewpoints to tackle condensate-linked pathologies like cancer, neurodegeneration, and viral infections, which intriguingly also associate with cytoskeletal changes.