Developmental Biology - Stem Cells|
Protein Stimulates Stem Cell Growth?
Investigators identify protein activating genes involved in generating embryonic stem cells...
The union of egg and a sperm initiates a complex process that ultimately yields a living being. All body cells come from embryonic stem cells that divide and give rise to organs and tissues. However, the way stem cells manage their accelerated divisions without losing control, as in tumors, and how the speed of cell division adapts to available molecular nutrients, are questions as yet unanswered.
Now, a group of scientists from the Centre for Genomic Regulation (CRG), Barcelona, Spain, and led by the Catalan Institution for Research and Advanced Studies (ICREA), professor Luciano di Croce and Eduard Sabidó, head of the CRG/UPF Proteomics Unit, have identified a molecular mechanism that regulates the speed at which stem cell divisions occur.
The work is published in the journal Science Advances, and could have a major impact on infertility research.
Researchers observed a previously unknown function of a protein known as AHCY or Adenosylhomocysteinase. AHCY regulates gene activation in embryonic stem cells. CRG scientists used molecular, cellular and computational tools to define proteins they identified as bound to the genome of embryonic stem cells.
"We managed to obtain a snapshot of the embryonic stem cell proteome [proteins associated with DNA] and that has provided us with a great deal of unexpected data," explains Sergio Aranda, junior researcher at CRG. "For example, we discovered the presence of certain metabolic enzymes, including AHCY, directly associated with gene regulation," he adds.
These new findings not only establish AHCY as an activation regulator, but point to a molecular association between nutrient metabolism and genomic regulation as controlling the speed of pluripotent stem cell division during embryo development — possibly affecting tumor cell growth as well.
"The presence of nutrients is essential for the embryo to grow properly. In our study, we identified at the molecular level, how this relationship between nutrient availability and embryonic stem cell division speed is established," explains Luciano Di Croce, Group Leader at CRG.
"We would now like to investigate a possible association between AHCY and defects during embryonic development in humans, as this would enable us to provide tools for molecular diagnosis and the prediction of possible fertility problems," adds CRG Staff Scientist, Sergio Aranda.
Profiling the chromatin-bound proteome (chromatome) in a simple, direct, and reliable manner might be key to uncovering the role of yet uncharacterized chromatin factors in physiology and disease. Here, we have designed an experimental strategy to survey the chromatome of proliferating cells by using the DNA-mediated chromatin pull-down (Dm-ChP) technology. Our approach provides a global view of cellular chromatome under normal physiological conditions and enables the identification of chromatin-bound proteins de novo. Integrating Dm-ChP with genomic and functional data, we have discovered an unexpected chromatin function for adenosylhomocysteinase, a major one-carbon pathway metabolic enzyme, in gene activation. Our study reveals a new regulatory axis between the metabolic state of pluripotent cells, ribosomal protein production, and cell division during the early phase of embryo development, in which the metabolic flux of methylation reactions is favored in a local milieu.
Most fundamental cellular functions rely on chromatin-based processes, such as transcription, replication, and inheritability of genetic and epigenetic information. In mammals, chromatin structures are spatially and functionally organized into compartments by the combination of strong and weak molecular interactions (1). To date, our knowledge on the distributions of chromatin-bound factors is limited to a reduced number of proteins and histone modifications (2, 3). Genomic, transcriptomic, and global proteomic profiling can only predict the proteomic composition of the cellular chromatin. Moreover, proteins lacking a chromatin/DNA recognition motif are difficult to foresee as chromatin-associated factors, thereby limiting their characterization. Hence, a simple, straightforward, and reliable “chromatomic” approach is in high demand to define the proteomic composition of the cellular chromatin and to discover unpredicted chromatin-associated factors de novo.
Sergi Aranda, Anna Alcaine-Colet, Enrique Blanco, Eva Borràs, Claire Caillot, Eduard Sabidó and Luciano Di Croce.
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Embryonic stem cells labeled with chromatin labelling reagent (EdU).
Image Credit: CRG 2019.