Mammalian development relies on the precise execution of highly coordinated cell-fate decisions by stem cells, which can undergo self-renewal, reversibly exit into a quiescent state, or terminally commit to a cell differentiation program. To orchestrate these decisions, stem cells make frequent use of ubiquitylation, an essential post-translational modification that alters the stability, activity, localization, or interaction landscape of target proteins. Our lab leverages the strength of the NIH intramural program, by combining our core expertise in human pluripotent stem cell culture, proteomics, and ubiquitin biochemistry with animal models, clinical genetics, and human disease cohorts. Our work has determined how ubiquitylation controls protein translation, cell division, and migration during differentiation and has uncovered mechanisms by which defects in ubiquitylation enzymes result in congenital diseases of impaired brain and craniofacial development or autoinflammation. We are continuing these studies to elucidate further basic principles of cell-fate specification and to provide insights into the molecular origin of human diseases, which will be useful for developing novel therapeutic approaches.
Dr. Achim Werner received his Ph.D. from the International Max Planck Research School for Molecular Biology in Göttingen, Germany. As a California Institute of Regenerative Medicine fellow, Dr. Werner then performed his postdoctoral work at the University of California, Berkeley, where he studied the role for ubiquitylation enzymes in human embryonic stem cell maintenance and differentiation. By combining mass spectrometry-based approaches with stem cell differentiation assays, biochemical techniques, and ribosome profiling, Dr. Werner’s work has elucidated a novel pathway that regulates the function of newly synthesized ribosomes to allow stem cells to adopt a neural crest cell fate during differentiation. On the basis of these findings, Dr. Werner was awarded an NIH/NIDCR K99 Pathway to Independence Award in 2015. In 2017, Dr. Werner launched his independent research program at NIDCR as Chief of the Stem Cell Biochemistry Unit. His lab combines biochemical and proteomic approaches with human pluripotent stem cell culture, clinical genetics, and human disease cohorts. This integrated approach has allowed his lab to uncover basic principles of how ubiquitylation controls cell-fate decisions during differentiation and how defects in ubiquitylation enzymes results in human diseases such as autoinflammation and developmental disorders.
- Asmar AJ, Abrams SR, Hsin J, Collins JC, Yazejian RM, Wu Y, et al. A tissue-specific ubiquitin switch coordinates early brain, craniofacial, and skin development. Nat Commun. 2023 Jul 26;14(1):4499. doi: 10.1038/s41467-023-40223-y.
- Ferrada MA, Savic S, Ospina Cardona D, Collins JC, Alessi H, Wilson L, et al. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis. 2022 Sep 29;140(13):1496-1506. doi:10.1182/blood.2022016985.
- Beck DB, Basar MA, Asmar AJ, Thompson J, Oda H, Uehara DT, et al. Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation. Sci Adv. 2021 Jan 20;7(4):eabe2116. doi: 10.1126/sciadv.abe2116.
- Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins J, Pei W, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Eng J Med. 2020 Dec 31;383(27):2628-2638.doi: 10.1056/NEJMoa2026834.
- Werner A, Iwasaki S, McGourty C, Medina-Ruiz S, Teerikorpi N, Fedrigo I, et al. Cell-fate determination by ubiquitin-dependent regulation of translation. 2015 Sep 24;525(7570):523-527. doi:10.1038/nature14978.