To those who spend countless hours on the lab bench, to those that wake up in the middle of the night to incubate samples, to those that re-run assay after assay, to those that persist through every grant application and peer review, to all who are proud to call themselves scientists, we say thank you. Your research does not go unnnoticed, and neither does your dedication, your passion, your lack of sleep, and your continued efforts to keep doing what you do. It's because of you and your work that we are closer each day to finding cures, saving lives and making the world better for all of us.
Scientists in the Spotlight
Dr. Jianchang Yang, MD, PhD Assistant Professor at Department of Surgery & Pathology
Stony Brook University Medical Center
Dr. Yang's research interests include the development of novel therapies for acute myeloid leukemia, using new approaches to killing leukemia stem cells; somatic cell reprogramming and the generation of patient-specific pluripotent progenitor cells for clinical therapies; and the development of stem cell therapies for use in transplantation and the management of various blood disorders.
SALL4 is a zinc finger transcription factor which plays a vital role in maintenance of stem cell identity and stem cell self-renewal through transcriptional repression. This study highlights a new mechanism by which SALL4 represses gene expression through interaction with DNMT’s - a previously unrecognized pathway. Furthermore it proposes that DNA methylation and histone deacetylation mechanisms act synergistically to contribute to the regulatory activities of SALL4. This study provides new insight into stem cell self-renewal mediated by SALL4 via epigenetic machinery.
Dr. Tania L. Roth, PhD Assistant Professor at Department of Psychological & Brain Sciences
University of Delaware
In her research lab at the University of Delaware, Dr. Roth and her team are interested in understanding how environmental factors, such as parenting behavior and social stress, can influence the development of behavior and psychiatric disorders. The lab's primary interests are centered on identifying epigenetic changes associated with early-life caregiving experiences, particularly maltreatment. To better understand the relationship between caregiver maltreatment, epigenetic marking of the genome, and behavioral outcomes, they utilize various molecular and behavior assays in developing and adult rats (males and females). They focus on multiple brain regions that play a significant role in behavior and mental health, and that are particularly susceptible to the damaging effects of early-life stress.
It has previously been reported that childhood abuse and neglect compromises neural structure and function which can lead to neurological and psychiatric disorders in adulthood. Likewise, it has also been shown that early life adversity may affect protein levels of brain-derived neurotrophic factor (BDNF), which is one of several factors mediating neural plasticity. Using a rodent model of infant maltreatment, this study showed methylation of BDNF DNA through the lifespan to adulthood resulting in reduced BDNF expression in adulthood. This condition however, could be rescued by chronic treatment with a DNA methylation inhibitor. “We demonstrate that not only do rodents that have experienced abuse grow up and mistreat their own offspring but that their offspring also have significant DNA methylation.” This study highlights the robust and enduring genetic imprint that results from childhood trauma which has lasting effects throughout the lifespan of an individual and into the next generation.
GlaxoSmithKline's EZH2 Biology Team Christine Thompson, Heidi Ott, Michael McCabe, and Susan Korenchuk
GlaxoSmithKline's EZH2 team strives to understand the role of EZH2 in cancer biology and to explore how EZH2 inhibitors may have therapeutic benefit in the clinic. These efforts have led to the development of GSK126, a selective and potent EZH2 inhibitor that is currently being investigated in a Phase I clinical trial in relapsed/ refractory DLBCL patients.
Featured Publication:
EZH2 Inhibition as a Therapeutic Strategy for Lymphoma with EZH2-Activating Mutations McCabe MT1, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra A 3rd, Diaz E, LaFrance LV, Mellinger M, Duquenne C, Tian X, Kruger RG, McHugh CF, Brandt M, Miller WH, Dhanak D, Verma SK, Tummino PJ, Creasy CL
(Cancer Epigenetics Discovery Performance Unit, Cancer Research, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania)
EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) involved in repression of gene expression through methylation of histone H3 on lysine 27 (H3K27). Activating mutations in EZH2 cause increased H3K27 trimethylation in a subset of diffuse large B-cell lymphomas (DLBCL) and follicular lymphomas. The authors have shown that a potent small molecule inhibitor of EZH2 methyltransferase activity, GSK126, is highly selective for EZH2 and effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and xenografts in mice. In addition to the potential therapeutic implications for EZH2 mutant lymphoma, GSK126 will also serve as a useful tool to understand the role of EZH2 methyltransferase activity which has previously been unattainable using conventional genetic techniques.
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