News from the Department of Epigenetics and Molecular Carcinogenesis
Cole Laboratory publishes new paper in Cell - Chromosome mis-segregation creates cells with the wrong number of chromosomes (aneuploid cells). In gametes (eggs and sperm), chromosome mis-segregation can lead to human aneuploidies like trisomy 21 that causes Down syndrome. Although it is well known that older mothers are more likely to give birth to children with Down syndrome, it is less well known that younger fathers are also more likely to parent a Down syndrome child. To understand this lesser known phenomenon, the Cole lab (Zelazowski M et al, Cell, 2017) has directly studied chromosome recombination during male meiosis in juvenile and adult mice. Recombination during meiosis results from programmed DNA breakage, subsequent DNA repair, and the formation of crossovers – a specific DNA repair product that exchanges DNA between parental chromosomes. Crossovers are essential for segregating the correct number of chromosomes into each gamete. The Cole lab found that fewer crossovers formed during juvenile waves of meiosis compared to adult waves, because juvenile waves of meiosis employ alternative DNA repair pathways that are less likely to generate crossovers. This discovery is important not only for understanding the origin of aneuploidy in sperm, but also for understanding how cells repair DNA, which is important because although errors in DNA repair can lead to cancer-causing mutations, they can also be exploited for the treatment of cancer. The paper will be available online (http://www.cell.com/cell/home), DOI: 10.1016/j.cell.2017.08.042, September 21, and in print, October 19.
Ellen Richie, Ph.D. and Collene Jeter, Ph.D. garner CPRIT funding for Flow Cytometry and Cell Imaging Core (8/16/17)
This new grant will support the Science Park Flow Cytometry and Cell Imaging core. It is anticipated that the award will be used to purchase a a new FACSAria III cell sorter, a Leica TCS SP8 multiphoton microscope, and a FAST Airyscan module to increase the utility of their current confocal microscope.
Santos earns prestigious awards
Margarida Almeida Santos, Ph.D. was named a 2017 American Society of Hematology (ASH) Scholar in November and a 2017 Andrew Sabin Family Fellow in March. The prestigious ASH Award supports fellows and junior faculty transitioning from trainee to independent investigator. The ASH award will be used to study the “Tumor promoting role of the DNA damage response in MLL-fusion leukemias.” The Sabin Family Fellows Award was established to encourage creative, independent thinking and high-risk, high-impact research at MD Anderson. Santos will use the award to investigate “The tumor promoting role of the DNA damage response.”
New study uses CRISPR technology to link a YEATS domain protein (ENL) to Leukemia (3/1/17)
Associate Professor Xiaobing Shi, Assistant Professor Hong Wen and collaborators David Allis and Scott Armstrong have shown that ENL, a YEATS domain containing protein that recognizes histone acetylation, is required for disease maintenance in acute myeloid leukemia (AML) (Wan L et al, Nature, 2017). Additionally, they showed that disrupting ENL led to anti-leukemic effects and exacerbated the sensitivity of leukemia cells to bromodomain and extra-terminal (BET) inhibitors, thus setting the ground work for developing ENL inhibitors as potential therapeutics for AML.
Han Xu, Ph.D. joins department with CPRIT award (1/2/17)
Assistant Professor Han Xu, Ph.D., joined the faculty of the Epigenetics and Molecular Carcinogenesis department in January, arriving from the Broad Institute of MIT and Harvard. Xu received his Bachelor of Engineering in Computer Science and Master of Engineering in Information Systems from Zhejiang University, China. Xu is developing computational algorithms for the design and analysis of high-throughput biological experiments with a focus on applications in transcriptional and epigenetic gene regulation. His current research emphasis is the optimization, design, and analysis of CRISPR-based genetic and epigenetic perturbation screens
Department raises money for Adopt a Family (1/2/17)
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.
Barton Lab discovers how stem cells maintain identity (12/1/16)
The Barton lab is leading the way in understanding the functions of non-coding RNAs, especially at the convergence of stem-cell biology and epigenetics. Previously, the Barton lab identified several small non-coding RNAs whose activation was mediated by p53. Now, they have identified long non-coding RNAs (lncRNAs) targeted by p53 (Jain A et al, Mol Cell, 2016). One of these, lncPRESS1, is required to maintain ESC identity and appears to act by binding to and sequestering the histone deacetylase SIRT6, thus preventing SIRT6 from deacetylating histone H3 at K9 and K56. H3K9ac and H3K56ac are enriched at the promoters of genes required to maintain pluripotency, and loss of these epigenetic marks correlates with stem cell differentiation. Future studies will be aimed at determining the site-specificity for this effect, that is, why the effects are seen specifically at pluripotency genes.
Bratton Lab advances understanding of how chemotherapies kill cells (11/24/16)
Apoptosis, or programmed cell death, is a means cells use to cause their own death. Toxic agents, like chemotherapeutics, trigger apoptosis by activating proteins called caspases. A protein complex known as the apoptosome helps activate caspases. The Bratton lab has revealed the underlying mechanisms that define the Apaf-1-caspase-9 apoptosome as a proteolytic-based molecular timer (Wu CC et al, Nat Commun, 2016). In doing so, they have provided the first direct evidence that caspase-9 forms both homo- and heterodimers within the apoptosome, each of which plays unique roles in the initial recruitment, activation, processing, and release of caspase-9 from the complex. Given the apoptosome’s critical role in the execution of stress-induced apoptosis, these studies provide key insights into the mechanisms by which many, if not most, chemotherapeutic agents induce cell death.
Johnson and Cole Labs uncover a new role for a tumor suppressor in DNA repair (11/15/16)
Work from the Johnson lab previously showed that E2F1, a critical transcription factor target of the retinoblastoma (Rb) tumor suppressor protein, localizes to sites of both UV and IR induced DNA damage in a phosphorylation dependent manner. At sites of UV damage, E2F1 recruits the histone acetyltransferase GCN5, which acetylates histone H3K9 in order to open chromatin structure and increase accessibility to the damaged site by the DNA repair machinery. Now they have shown, in cooperation with the Cole lab, that E2F1 recruits not only Rb, but also BRG1 (the ATPase subunit of the chromatin remodeler SWI/SNF) to sites of DNA double-strand breaks, where they promote DNA end resection and homologous recombination (HR) (Velez-Cruz et al, Genes Dev, 2016).
Stellar students land GSBS scholarships and awards
Aundrietta Duncan (Barton Lab) - R. W. Butcher Achievement Award.
Aimee Farria and Sharon Dent (Dent Lab) - Andrew Sowell-Wade Huggins Professor and Fellow Award.
Sitaram Gayatri (Bedford Lab) - Wei Yu Family Endowed Scholarship.
Rhea Kang (Cole Lab) - City Federation of Women’s Clubs Endowed Scholarship in Biomedical Sciences.
Nicolas Veland (T. Chen Lab) - Andrew Sowell-Wade Huggins Scholarship in Cancer Research.
Science Park Next Generation Sequencing Core funding is renewed (9/14/16)
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.
Santos named Kimmel Scholar (4/11/16).
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.
Tang lab links normal stem cells to aggressive prostate cancer (2/29/16).
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.
Two Faculty Members, Xiaobing Shi and Sharon Dent, honored at the President's Recognition for Faculty Excellence event (2/24/2016).
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."
Professor and Chair, Sharon Dent Interviewed for "People and Ideas" feature in the Journal of Cell Biology (1/4/16).
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.
Professor Michelle Barton Elected as Fellow of the American Association for the Advancement of Science (AAAS) (11/24/15).
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.
Assistant Professor Francesca Cole Awarded NIH Director's New Innovator Award (10/6/15)
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.
Professor Richard Wood Interviewed on NPR Regarding the 2015 Nobel Prize in Chemistry for DNA Repair (10/7/15).
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.
Professor David Johnson Takes on GSBS Faculty Presidency (9/17/15)
David Johnson, Ph.D. took over his new role as GSBS Faculty President, replacing Vasanthi Jayaraman, Ph.D., at the GSBS faculty meeting on September 17, 2015.
ATP-dependent chromatin remodeling complexes regulate non-chromatin targets (3/15/15; 6/4/15)
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
Role of SAGA, a histone acetylase complex, in reprogramming fibroblasts to a stem cell state defined (4/15/15)
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
CARM 1 promotes nuclear export of special class of RNAs (3/15/15)
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
YEATS protein potential therapeutic target for cancer (10/23/2014)
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
Tumor-suppressor connects with histone protein to hinder gene expression (4/10/2014)
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
Protein duo thwarts chromosomal scrambling and DNA breakage (2/11/2014)
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
Science Park Employees Walk Over 20,000 Miles as Part of Fitness Program (1/8/2014)
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 Receives Sanofi-Cell Research Outstanding Paper Award (11/04/2013)
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.
"Jekyll and Hyde" Protein Offers New Route to Cancer Drugs (09/27/2013)
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.
Study Uncovers Actin's Action in the Nucleus (03/25/2013)
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.
Chromatin Gets a Makeover (01/31/2013)
Dr. Sharon Dent and Dr. David Johnson, faculty from the Department of Epigenetics and 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.
Prostate Cancer Stem Cells Emerge from Low-PSA Cells (05/03/2012)
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.
UT MD Anderson Scientists Discover Secret Life of Chromatin (08/30/2011)
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.
UT MD Anderson Preclinical Research Boosts Case for New Drug Approach (01/16/2011)
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.
Researchers Find Melanoma Not Caused by Early UVA Light Exposure (05/2010)
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.