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HSCI Science Update: October 2011

October 26, 2011

  • Getting the Motors Running

    The mammalian central nervous (CNS) is made up of several distinct neuronal subtypes, each with different characteristics and susceptible to unique degenerative stimuli. Understanding the CNS as a whole requires a deep investigation of each of these subtypes, but isolating human neurons can be difficult for several reasons. While embryonic stem cell-derived neurons have shown great promise, many seem to only superficially resemble their native counterparts, lacking the unique characteristics of the subtype in question. Recent work from HSCI Principal Faculty Kevin Eggan overcomes these challenges by bypassing the embryonic stage and directly inducing the conversion of adult fibroblasts (cells that produce the structural tissue called collagen) into motor neurons (MNs). By forcing the expression of a specific set of genes, Eggan's team was able to produce functioning MNs that behave as those derived naturally in the body. These induced MNs provide a valuable population for investigating the development, function, and degeneration of one neuronal subtype. The team expects that similar strategies may work for other neuronal subtypes as well.

    Son, E.; Ichida, J.; Wainger, B.; Toma, J.; Rafuse, V.; Woolf, C.; Eggan, K. (2011) Conversion of Mouse and Human Fibroblasts into Functional Spinal Motor Neurons. Cell Stem Cell 9, 205-218.
     

  • Loop-the-Loop

    A phenomenon called "chromatin looping" occurs when the structural material that encases DNA (chromatin) forms a loop, bringing distant genes closer to promoters that reside far away on the genetic strand. Chromatin looping was initially observed in 2002 but recent work from HSCI Principal Faculty Daniel Tenen is the first to identify a specific protein whose job is to facilitate this process. Scientists have long known that the protein RUNX1 helps stem cells become hematopoietic stem cells (HSCs), the precursors to blood cells, but until now the details of this mechanism were still unclear. Tenen and his team chose to probe RUNX1 for its interactions with DNA in mice. They found that the protein binds to an area of the genome far away from a gene called CD34 whose expression gives HSCs their distinctive character. When RUNX1 is not allowed to bind to this promoter area, CD34 is not expressed and stem cells do not become HSCs. They also found evidence that the other proteins in the RUNX family may facilitate other chromatin loops, suggesting that RUNX proteins may play a more general role in mediating these kinds of interactions. With this information, scientists can probe the RUNX1 protein and others in the RUNX class for genetic mutations that lead to various blood diseases.

    Levantini, E.; Lee, S.; Radomska, H.; Hetherington, C.; Alberich-Jorda, M.; Amabile, G.; Zhang, P.; Gonzalez, D.; Zhang, J.; Basseres, D.; Wilson, N.; Koschmieder, S.; Ebralidze, A.; Bonifer, C.; Okuno, Y.; Gottgens, B.; Tenen, D. (2011) RUNX1 regulates the CD34 gene in haematopietic stem cells by mediating interactions with a distal regulatory element. EMBO Journal Epub 2011 August 26.
     

  • Get Out the Map

    DNA is widely known as the primary map for a developing organism, giving directions about which proteins will or will not be produced. But recent studies have revealed a second layer of information acting on top of the DNA, a set of “epigenetic”  forces that are not caused by the underlying DNA sequence that further regulate gene expression. Chromatin looping is one such force. Another, called gene imprinting, is the result of physical and chemical additions to the DNA which allow either the maternally or paternally contributed gene to be expressed, but not both. Recent work from HSCI Executive Committee member Carla Kim introduces yet another list of directions for the DNA map when it comes to the role of imprinted genes. Kim and her team show that a protein called BMI1 regulates the expression of imprinted genes and that this regulation is necessary for the normal functioning of lung stem cell populations. Precise control of proteins encoded by imprinted genes was required for lung cell self-renewal and was lost in mutant cells that lacked BMI1. This greater understanding of lung stem cell regulation may, in the future, allow researchers to manipulate them to help treat injury and disease.  Kim’s work also shows that the regulation and function of imprinted genes is crucial to self-renewal mechanisms across a variety of tissue types.

    Zacharek, S.; Fillmore, C.; Lau, A.; Gludish, D.; Chou, A.; Ho, J.; Zamponi, R.; Gazit, R.; Bock, C.; Jager, N.; Smith, Z.; Kim, T.; Saunders, A.; Wong, J.; Lee, J.; Roach, R.; Rossi, D.; Meissner, A.; Gimelbrant, A.; Park, P.; Kim, C. (2011) Lung Stem Cell Self-Renewal Relies on BMI1-Dependent Control of Expression at Imprinted Loci. Cell Stem Cell 9, 272-281.