Unlocking the Ribocode

An artist’s rendition of a ribosome. Credit: C. BICKLE/SCIENCE

Genes to Genomes asked Dr. Maria Barna (Stanford University), a recipient of the Rosalind Franklin Award for Young Investigators, to tell us about her research and what it means to receive the award. She will be recognized for her Rosalind Franklin Award along with the other 2016 recipient, Dr. Carolyn McBride, at the 2015 American Society of Human Genetics meeting this week.

It is an incredible honor to be selected as the recipient of a 2016 Rosalind Franklin Young Investigator Award. I am so grateful to be receiving this prestigious award, and I hope to follow in the footsteps of all the amazing women scientists who have received it before me. This award will be extremely helpful in supporting our research as we delve deeply into an exciting, newly-discovered mechanistic program for controlling how the mammalian genome is converted into final effector proteins, which execute all of the decisions that a cell makes during its life. The central dogma of biology, which Rosalind Franklin was so instrumental in establishing, has for decades served as an explanation for the flow of genetic information within a biological system. In our current understanding of the “normal” flow of biological information from DNA to RNA to protein, the ribosome—the central protein synthesis machinery of the cell—decodes the genome with machine-like precision, serving as an integral but largely passive participant in the synthesis of effector proteins across all kingdoms of life (whether a cat, carp, cholera or Caesar).

There are millions of ribosomes situated in every cell’s cytoplasm, churning out the proteins essential for cellular life. To a large extent , the ribosome has been viewed as a backstage participant in translating the genetic code, despite being recognized as spectacular molecular machine. Our research has fundamentally changed this view by demonstrating that not all of the millions of ribosomes within each cell are the same, and that ribosome heterogeneity provides a novel means for diversity of the proteins that can be produced in specific cells, tissues, and organisms from the same DNA sequence. Collectively, we have termed this additional layer of gene regulation as a “ribocode,” which adds important diversity to how gene products can be converted into proteins in time and space.

I believe that this interesting discovery has been made possible through mouse genetics. By employing an unbiased forward genetic screen, we realized that the activity of core components of the ribosome machinery were unexpectedly tailored to execute highly specific developmental decisions and were “tuned” to translating specific subsets of key developmental mRNAs. My favorite example comes from a mouse mutant we first characterized which harbored a loss-of-function mutation in one of the 80 ribosomal proteins (RPs) that constitute the core of the mammalian ribosome, known as RPL38. It was extremely unexpected when we discovered that RPL38  was selectively required for the formation of the mammalian body plan. In Rpl38 mutant mice, the stereotyped arrangement of vertebral elements were altered in a profound way, including the formation of extra pairs of ribs growing out of vertebrae in the neck! This led to the realization that RPL38 can be considered a regulatory element, or “filter,” of the ribosome—one that is selectively required to convert a subset of critical genes into the proteins, including a key group of  Homeodomain transcription factors  that establish  the body plan.

Since I started as an Assistant Professor at Stanford, my laboratory has taken a highly genetic approach to deconstructing the impact of individual ribosome components on the translational code of gene expression in specific cell and tissue types. At present, we are creating one of the largest series of conditional knock-out mice for each of the 80 core RPs belonging to the mammalian ribosome. Our findings have uncovered distinct and striking tissue-specific phenotypes, which are evident upon conditional deletion of specific RPs, during eye development, facial patterning, limb development, and spermatogenesis, among many others. An additional outstanding question raised by our initial studies is the nature of regulatory elements in target mRNAs that interface with what we called “specialized ribosomes,” which may contain a unique RP composition and/or activity. Akin to a transcription factor binding site or micro-RNA seed sequence, how might ribosome-mediated control of gene regulation be encoded within the sequence and structure provided by the transcribed genome? We recently identified unique structured elements within the untranslated regions of transcripts that are recognized by specialized ribosomes. We are starting to understand the grammatical rules for how such elements guide the ribosome in decoding the genome with newfound specificity.  We anticipate that this ‘ribocode’ will be a vital  additional layer of gene regulation guiding cell specification, tissue patterning, mammalian development, and human disease—that  my laboratory hopes to study for decades to come.

I’m extremely excited by the recognition and support given to our work by the Rosalind Franklin Young Investigator Award. This recognition is particularly meaningful to me, as my lab has embarked on work that was initially perceived as very provocative and potentially too risky. As with any research that breaks convention or dogma, my lab has worked tirelessly to explore largely uncharted areas of research into gene regulation. Our investigations have always been aided by the elegance and strength of mouse genetics, which has the power to overturn what we think is known and what is still left to be discovered. I’m particularly grateful for the extraordinary cadre of junior scientists in my lab that make this research possible and who, in many ways, follow the pioneering spirit for discovery embodied by Rosalind Franklin.

Dr. Barna received her bachelor’s degree in anthropology from New York University and her PhD in molecular biology from Cornell University and Sloan-Kettering Institute. Her doctoral research focused on the genetic basis of limb development. Building on her post-doctoral research conducted at the University of California, San Francisco, Dr. Barna currently studies the ribosome molecular machine in her own laboratory at Stanford University.

The views expressed in guest posts are those of the author and are not necessarily endorsed by the Genetics Society of America.