The power of micropeptides in brains and society
Posted by Valerie Tornini, on 18 December 2023
Throughout my years in science, I have been drawn to biological questions across scales and have been struck by how often they reflect aspects of societal phenomena. In this piece, I share with you some of my recent work, and how I view it as a lesson on how reductive or myopic definitions can overlook some of the most impactful discoveries and individuals in a collective.
Like many developmental biologists, I am fascinated by our bodies’ extraordinary cell type diversity. The genetic and epigenetic codes in each type of cell will dictate which unique sets of proteins are expressed. Until recently, the role of a large class of genes, now called micropeptides (or microproteins), was largely overlooked. Protein-coding genes were initially defined using a size cutoff of 100 codons; proteins smaller than that were assumed to not fold properly or carry out functions. Starting in 1990, we realized that this biased definition was filtering out potentially functional genes 1–3. Partnered with technological advances, this shift in mindset has allowed the identification of thousands of small open reading frames (sORFs) that may encode functional tiny proteins.
In recently published work, my colleagues and I set out to investigate whether some previously identified long noncoding RNAs in fact encoded micropeptides 4–6. Many of these RNAs were enriched in developing zebrafish brains and could represent uncharacterized small proteins that play important roles in vertebrate neurodevelopment. If this were the case, the loss of these micropeptides could manifest as behavioral phenotypes, a useful means of screening and prioritization. In this study, we showed that two previously identified long noncoding RNAs actually encode micropeptides with homology to a chromatin regulator found exclusively in vertebrates, called Hmgn1. In humans, this chromatin architectural protein is critically overexpressed in Down syndrome 7, and has been identified as a gene linked to autism 8. Through a series of behavioral, pharmacological, cellular, and molecular assays, we found that when these micropeptides were mutated, the gene regulatory networks that establish cerebellar cells and oligodendrocytes were most significantly affected. Intriguingly, these cell types were recently proposed to have appeared and evolved in jawed vertebrates 9. Is it possible that the emergence of these micropeptides co-evolved with the gene regulatory networks that established cerebellar and oligodendrocyte cell types in vertebrates 10–12? This is yet an open question.
Recently, there has been a renewed urgency to understand the existence and vast possible functions of micropeptides, particularly in the brain 13–15. Although there is evidence for thousands of putative micropeptides, the validation and characterization of these proteins will require high-throughput efforts across species, conditions, and cell types 16. Key implications from this field include identifying therapeutic or cell targets for neurodevelopmental diseases or disorders; engineering strategies for therapies directed towards de novo protein or drug design; and identifying molecular strategies for co-evolution of chromatin regions that harbor cryptic ORFs in physiologic, stressed, or disease neural states.
As I was working on this problem, I reflected on what drew me to my fascination with small proteins to begin with. I realized that the scientific question appealed to me because I saw myself and so many of my colleagues in this story. Consider the arbitrary limits placed on the definition of a protein. Evidence for, and acceptance of, changed definitions across fields has enabled a whole world of genes to now be deemed worthy of investigation. As such, this work comes at a time not only of scientific innovation, but also of social transformation. What are we missing when we limit our definitions to only the most dominant, visible, acceptable, status quo? What creativity has been ignored or stifled because it didn’t fit the mold? What are the outsized roles of the forces that shape creative strategies of survival – even thriving – and evolution?
This work also got me thinking about the evolutionary history of these micropeptides 17, and how gene networks and cell types may have co-evolved. Thinking about some of the ways that these micropeptide genes emerge, adapt, evolve, or disappear in different contexts provided me a lens through which to understand and confront some of the societal challenges that the life sciences – and academia at large – are, and have been, facing worldwide 18–21. Around the time I was wrapping up this work on micropeptides in zebrafish neurodevelopment 6, the NASEM report on “Advancing Antiracism, Diversity, Equity, and Inclusion in STEMM Organizations: Beyond Broadening Participation” was published 21. In particular, one section drew my attention:
“…the noteworthy ways in which [minoritized] individuals respond to bias in STEMM environments…can be categorized into three general groups: exiting the field, implementing strategies to fit in, and collectively mobilizing to transform the STEMM environment.” 21
How individuals respond to persistent, systemic biases in their environments – exit, adapt, or mobilize – is reflected in what often occurs in biological systems 22,23. Our environments and lived experiences inevitably shape the scientific questions that we ask, how we ask them, and who gets to ask them. The confluence of this report and my own scientific journey highlighted to me how impossible it is to remove ourselves – the experiences and environments of the people doing the science – from the science itself.
So, what are the “micropeptides” in your own work, in your story? I iteratively reflect on these questions both as a basic (neuro)developmental biologist and as an emerging bioethicist 24. As scientists, we can learn from the many unexpected discoveries regarding micropeptides – and any number of yet undervalued fields – to reimagine the tiny changes that can influence entire systems. When they are taken together, they’re not so small after all.
Acknowledgements
In reverse alphabetical order by first name (perhaps you can guess why from my own name), I am grateful to V. Greco, L. Grmai, L. Miao, L. Weiss, E. Strayer, C. Bartman, and A. Giraldez for feedback and/or workshopping through some of these ideas. I am supported by an award from the U.S. Eunice Kennedy Shriver National Institute of Child Health and Human Development (5K99HD105001).
Author Information
Valerie Tornini is currently an associate research scientist at Yale School of Medicine, and an incoming assistant professor in the Department of Integrative Biology and Physiology and the Institute for Society and Genetics at the University of California, Los Angeles (UCLA), USA.
References
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