News from the Department of Epigenetics and Molecular Carcinogenesis
Associate Professor Xiaobing Shi, Assistant Professor Hong Wen and collaborators David Allis and Scott Armstrong showed that ENL, a YEATS domain containing protein that recognizes histone acetylation, is required for disease maintenance in acute myeloid leukemia (AML). Further, disrupting ENL led to anti-leukemic effects and exacerbated the sensitivity of leukemia cells to bromodomain and extra-terminal (BET) inhibitors, thus setting the groundwork for developing ENL inhibitors as potential AML therapeutics.
The Houston-based laboratories of Michelle Barton, Ph.D. and Xiaobing Shi, Ph.D., raised $925 to help brighten the holiday season for the families of patients undergoing treatment at MD Anderson. In addition, Rebecca Deen, Jennifer Crunk and Sandra Smith who work on the Smithville Campus, raised an additional $532 by contributing wreaths to the annual Wreath Auction.
Professor Jianjun (JJ) Shen has obtained a $5 million grant from the Cancer Prevention and Research Institute of Texas (CPRIT) to support the Next Generation Sequencing Core that he directs. This core has prepared and sequenced >3200 libraries, including total RNA, mRNA, miRNA, DNA methylation, ChIP-Seq and exome libraries, for nearly 40 user group members (including 10 early career investigators) from seven distinct Texas institutions.
Margarida Almeida Santos, Ph.D., was named one 15 Kimmel Scholars. The Sidney Kimmel Foundation, which made the $200,000 award, supports promising early-career cancer researchers. The award will support her research targeting protein arginine methylation in MLL-fusion acute myeloid leukemia.
This study, led by instructor, Dingxiao Zhang, Ph.D., in Professor Dean Tang's lab, shows that adult stem cells exist in the basal cell layer of human prostate and that these cells express a cohort of genes that overlap with those expressed in the most aggressive and deadliest prostate cancers. In addition, Tang lab studies have provided the basis for treating advanced and androgen resistant prostate cancers with inhibitors that target DNA polymerase I and the oncogene, MYC. These findings were published in Nature Communications.
Dr. Shi received one of five Faculty Scholar Awards, given to recognize early career excellence. Dr. Dent received one of two inaugural R. Lee Clark Prizes, bestowed for exemplifying "the spirit of our institution's first president."
Sharon Dent, Ph.D., gave a brief interview and research retrospective in the January 4, issue of JCB. In it she talks about her longstanding interests in chromatin, transcriptional control and epigenetics.
Michelle Barton, Ph.D., was nominated and elected by her scientific peers in recognition for her contributions to understanding the function of the tumor suppressor, p53 in stem cells, particularly with respect to the discovery of TRIM24, an E3-ligase and epigenetic regulator that is overexpressed in many cancers. AAAS is the world's largest scientific society.
Francesca Cole, Ph.D., was recently named one of 41 NIH New Innovator Award Recipients for 2015. The New Innovator Award supports exceptionally creative new investigators who propose highly innovative projects that have the potential for unusually high impact. Dr. Cole's project, "Mechanistic Derivation of Germ Line Mutation by Genome-Wide Mouse Tetrad Analysis," will help define the global patterns of de novo germ line mutations and the frequencies at which such mutations occur in mice, with the long term goal of understanding the molecular mechanisms underlying germ line mutagenesis and developing strategies to prevent or treat disorders caused by such mutations. This award provides $2.4M in total costs.
Rick Wood, Ph.D., a well-known figure in the field of DNA repair was interviewed by NPR affiliate WBUR, in Boston, regarding the Nobel Prize in Chemistry awarded for "Mechanistic Studies of DNA Repair." The prizes were awarded to Tomas Lindahl, Paul Modrich and Aziz Sancar. Dr. Wood has previously worked in the laboratory of Nobel Laureate Tomas Lindahl.
David Johnson, Ph.D. took over his new role as GSBS Faculty President, replacing Vasanthi Jayaraman, Ph.D., at the faculty meeting on September 17, 2015.
Two recent studies by lead author Pabodh Kapoor, Ph.D., a postdoctoral fellow in Xuetong Shen's lab, have defined novels roles for chromatin remodelers. In the first study, Kapoor and collaborators from the laboratories of Drs. Guang Peng, Blaine Bartholomew and Jeff Ranish found that SWI/SNF, known to be important for remodeling chromatin, is also important for activating the DNA damage response.Genes Dev. 2015 Mar 15;29(6):591-602. In a second study, published in Molecular Cell, Kapoor with collaborators from the laboratories of Drs. Guang Peng and Mark Bedford showed that the INO80 chromatin remodeling complex helps regulate a Rad53 mediated DNA damage checkpoint. Mol Cell. 2015 Jun 4;58(5):863-9. These studies may lead to novel strategies to target DNA damage response and checkpoint proteins as well as chromatin remodeling pathways in cancer treatment
A collaboration between Dr. Sharon Dent and Dr. Jeff Wrana at the Lunenfeld-Tanenbaum Research Institute, has shown that Myc drives expression of the SAGA component Gcn5. Together, Myc and Gcn5, a histone acetyltransferase, reprogram fibroblasts to a stem cell state by activating an alternative splicing network. This collaboration also showed that Gcn5 is important for Myc-mediated stem cell self-renewal in embryonic stem cells. These findings raise the possibility that Myc-Gcn5 could also work together to promote tumor formation. Genes Dev. 2015 Jun 15;29(12):1341
Assistant Professor Donghang Cheng, Ph.D. in Dr. Mark Bedford's group was the co-corresponding author on a study demonstrating that in the absence of the arginine methyltransferase CARM1, a certain class of protein encoding RNAs remain in the nucleus. These mRNAs, which contain inverted repeats of the short interspersed nuclear element Alu in their 3' untranslated regions (IRAlus), are retained in nuclear bodies known as paraspeckles. CARM1 promotes their export from the nucleus via a dual mechanism. Genes Dev 2015 Mar 15;29(6):630-45
The Shi lab has found a new protein reader of modified proteins. The YEATS domain of AF9 recognizes acetylated histones. It was previously thought the only readers of acetyl groups were bromodomains. Bromodomains have long been a target of cancer therapuetic development, and the YEATS domain may now provide a new avenue for the development of future therapeutic targets. Cell. 2014 Oct 23;159(3):558-71
Dr. Hong Wen, an Assistant Professor in Xiaobing Shi's lab found that the protein ZMYND11 recognizes a special mark on another protein that helps package and protect DNA, the histone variant H3.3. When histone H3.3 is methylated, ZMYND11 recognizes and binds to the methylation mark to turn off a gene expression program that helps tumors grow. Nature. 2014 Apr 10;508(7495):263-8
A new study by Dr. Mark Bedford establishes a link between the TDRD3 protein and an enzyme that unwinds DNA at regions of active gene expression. The study provides evidence that this partnership can prevent DNA breakage and chromosomal translocations – two of the hallmarks of cancer. Mol Cell. 2014 Feb 6;53(3):484-97
A group of 72 Science Park employees participated in Walk Across Texas, a program that encourages regular physical activity. The teams collectively walked a total of 20,970 miles over an 8-week period, far surpassing their goal of walking 830 miles – the distance between El Paso and Beaumont.
Dr. Dean Tang of the Department of Epigenetics and Molecular Carcinogenesis received the 2012 Sanofi-Cell Research Outstanding Review Article Award for his review paper entitled, “Understanding cancer stem cell heterogeneity and plasticity," published in March, 2012. The article describes current research into the relationship between cancer cell heterogeneity and tumor development.
Researchers in Dr. Mark Bedford's lab collaborated on a study that identified distinct types of arginine methylation marks on E2F-1, a protein with opposing roles in both cell proliferation and apoptosis. Because the growth-promoting "Mr. Hyde" version of E2F-1 is implicated in most cancers, blocking the switch to this form could provide a new target for cancer treatment. Mol Cell. 2013 Oct 10;52(1):37-51.
The function of nuclear actin has stumped scientists for several decades. In a study featured on the cover of Nature Structural and Molecular Biology, investigators in Science Park faculty member Dr. Snow Shen's lab uncovered one of the protein's key nuclear functions. Nat Struct Mol Biol. 2013 Apr;20(4):426-32.
Dr. Sharon Dent and Dr. David Johnson, faculty from the Department of Molecular Carcinogenesis and Center for Cancer Epigenetics, review a number of recent studies highlighting chromatin's role as both receiver and transmitter of signals in various cell functions. Cell. 2013 Feb 14;152(4):685-9.
Science Park faculty member Dr. Dean Tang led a study that for the first time separated low-PSA and high-PSA prostate cancer cells, which led to the discovery of a low-PSA population of cancer stem cells that appears to be an important source of castration-resistant prostate cancer. Cell Stem Cell. 2012 May 4;10(5):556-69.
A team of researchers directed by Dr. Sharon Dent, director of the Department of Epigenetics and Molecular Carcinogenesis and Center for Cancer Epigenetics, investigate a signaling activity of chromatin that is independent of its central role in gene transcription. Cell. 2011 Sep 2;146(5):709-19.
A research team led by Dr. Dean Tang of Science Park reported that a microRNA inhibits prostate cancer metastasis by suppressing a surface protein commonly found on prostate cancer stem cells.
Investigators from Dr. David Mitchell's lab at Science Park reported that early life exposure to ultraviolet A light does not cause melanoma in a fish model that previously made that connection.