Oncogenic protein helps stem cells to remain pluripotent
The key factor preserving the identity of stem cells has been identified
LifeSciencesToday based on NYU Langone: Scientists Identify Key Factor that Maintains Stem Cell IdentityA protein associated with the development of several types of cancer appears to play a key role in the preservation of stem cells in an immature pluripotent state.
This is evidenced by the results of a study conducted by scientists from the Langone Medical Center of New York University (NYU Langone Medical Center), published in the open access journal Cell Reports (Raffaella Di Micco et al., Control of Embryonic Stem Cell Identity by BRD4-Dependent Transcriptional Elongation of Super-Enhancer-Associated Pluripotency Genes).
In the world of cells, stem cells are eternal "teenagers" whose fate has not yet been determined. In principle, they can be reprogrammed into any type of mature differentiated cells, which gives hope for their use for tissue and organ regeneration. However, the biology of stem cells requires a more complete understanding.
"Our discovery deepens the understanding of the multicomponent regulation of the state of stem cells," says Eva M. Hernando–Monge, PhD, associate Professor of Pathology, researcher at the Kimmel Center for Stem Cell Biology (Helen L. and Martin S. Kimmel Center for Stem Cell Biology) of the Langon Medical Center.
The newly identified stem cell factor BRD4 is a protein associated with several types of cancer and the target of promising drugs currently undergoing clinical trials. In 2013, Dr. Hernando-Monge and her colleagues found that BRD4 is overexpressed in melanoma cells and helps support their proliferation, while inhibiting BRD4 significantly slows down the growth of cancer cells. Apparently, this protein induces cancer, keeping, in particular, cancer cells in a relatively immature state, close to the state of stem cells. Intrigued, Dr. Hernando-Monge decided to find out what role BRD4 plays in real stem cells.
In her new study, Hernando-Monge suppressed BRD4 activity in mouse and human embryonic stem cells using BRD4-blocking compounds developed by Ming-Ming Zhou and his colleagues from the Icahn School of Medicine at Mount Sinai Medical Center. In addition, the researchers used special RNA molecules that block BRD4 gene transcripts. They observed the exit of cells from the stem state: during division, the cells began to demonstrate the characteristics of young neurons. According to scientists, stem cells remain dormant until a certain signal causes them to divide, producing differentiated highly specialized cells.
After inhibition of one of the key proteins
these embryonic stem cells have undergone differentiation and lost their pluripotency.
Cell nuclei are shown in green; nuclei expressing pluripotency factors are shown in blue and red.
Photo: Raffaella Di Micco, PhD.
As is known, BRD4 regulates the activity of genes by binding to the supporting structure of DNA – chromatin – in special areas-switches – superenhancers – scattered throughout the genome. These sites appear to be top-level regulators organizing characteristic expression patterns of several genes that together determine the identity of a cell, for example, a neuron or a myocyte.
"We found that BRD4 captures the super–enhancer sites of genes important for preserving the identity of stem cells," says Raffaella Di Micco, the first author of the paper. Treatment of stem cells with BRD4 inhibitors caused a sharp decrease in the expression of these genes, including OCT4 and PRDM14.
"OCT4 suppresses differentiation into neurons, so we think that the loss of this repression when BRD4 is inhibited is the most likely cause of induction in stem cells of neuronal characteristics," continues Dr. Di Micco.
OCT4 is one of four factors in the standard OKSM cocktail used to reprogram somatic cells into induced pluripotent stem cells (iPSCs). New data suggest that BRD4 "forces" the stem cell to change its identity from an even higher regulatory level.
"Theoretically, we could replace one or more of the OKSM factors with BRD4 protein or add it to a cocktail to increase the efficiency of reprogramming. And that's what we're working on right now," says Dr. Hernando–Monge.
Conversely, the scientist notes, BRD4 inhibitors can be used to reprogram cells in the opposite direction, for example, to transform stem cells into young neurons, which may one day be used in regenerative medicine.
Portal "Eternal youth" http://vechnayamolodost.ru06.10.2014