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Feb 1, 2012 (Vol. 32, No. 3)

Exploring the Role of Epigenetics

  • Burgeoning Field

    Recent years have opened an exciting time for epigenetics research, particularly with respect to development.

    “The epigenome is labile during periods of rapid cell division, and a change during that time is more likely to impact the organism. It may also be the ideal place for intervention,” pointed out Alicia K. Smith, Ph.D., assistant professor in psychiatry and behavioral sciences at Emory University.

    Dr. Smith and colleagues recently reported differences in neonatal CpG methylation that are specific to gestational age, and are present even in term deliveries.

    “It is known that DNA methylation patterns change as a person ages, but no study to date has shown such extensive differences over the weeks prior to delivery,” said Dr. Smith.

    The causal link between lower gestational age and the predisposition, over the course of the lifespan, to neuropsychiatric disorders and adult onset complex diseases has been known for several years, and these novel findings open the intriguing possibility that DNA methylation patterns may contribute to this association.

    “The central question is whether the different DNA methylation patterns that we see at different gestational ages are stable, and would predispose to detrimental health outcomes, or whether they continue to change as the individuals age,” explained Dr. Smith.

  • Histone Methylation Inhibition

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    Allogeneic hematopoietic stem cell transplantation is a curative treatment for many hematological malignancies resistant to other therapies. This beneficial antitumor activity largely derives from the reconstitution of the normal donor hematopoiesis and immune cells in the diseased patient. Unfortunately, this antitumor immunity is tightly linked to a life-threatening graft-versus-host disease, confounding the efficacy of the procedure. A novel and clinically relevant strategy has been developed by targeting histone methylation, which controls the survival and expansion of effector T cells, to selectively control ongoing graft-versus-host disease while preserving the beneficial antitumor effects.

    One of the severe complications following allogeneic hematopoietic stem cell transplantation, and a major limiting factor shaping their outcome, is graft-versus-host disease, which occurs when effector T cells from the donor tissue orchestrate an immune-mediated attack against recipient tissues.

    Graft-versus-host disease, an important cause of morbidity and mortality among transplant recipients, frequently represents a life threatening complication for which very limited therapeutic options are available at present. One of the relatively successful strategies is the use of steroids, but only about 40% of the patients respond and, overall, severe graft-versus-host disease is refractory and may be fatal in approximately 60% of the patients.

    Graft-versus-Host Disease

    Yi Zhang, M.D., Ph.D., assistant professor at the University of Michigan School of Medicine, and colleagues recently showed in a mouse model of graft-versus-host disease that administration of 3-deazaneplanocin, a histone methylation inhibitor, stopped the accumulation of alloreactive effector T cells after allogeneic bone marrow transplantation.

    The effect was associated with the selective activation of pro-apoptotic pathways in activated T cells, and was seen even after the disease had already been fully established.

    “It looks like the inhibition of histone methylation in activated T cells can immediately control the ongoing graft-versus-host disease, and this has never been achieved before,” said Dr. Zhang.

    While steroids weaken the ability of the donor T cells to launch an immune attack, and provide an effective therapeutic strategy for graft-versus-host disease, they also impair the other T cells. One key observation was that 3-deazaneplanocin did not inhibit the antileukemia activity of the donor T cells.

    “Our strategy, which modulates histone methylation but does not impair the immune cells undergoing homeostasis, allows to maximally protect naïve or standby immune cells from the inhibitor, and this is another beauty of our approach,” noted Dr. Zhang.

    Modulating histone methylation could provide a novel therapeutic approach not only for graft-versus-host disease, but for other medical conditions as well.

    “Given the profound effect of these inhibitors on the allogeneic T cell response, it could be possible to control other inflammatory disorders, such as graft rejection, which is an allogenic T cell response occurring in a different context, or autoimmune diseases, which most frequently have autoreactive T cells that are activated by self-antigens,” said Dr. Zhang.

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