Taking a basic science research approach to understanding cancer
Our research aims to define the mechanisms that control normal cell proliferation, differentiation, survival and genome maintenance to identify the aberrations in these processes that drive cancer. Our research focus areas include: Cellular and Molecular Mechanisms of Carcinogenesis; Cancer Genetics and Epigenetics; Genome Integrity - DNA Replication, Recombination and Repair; and Cancer Stem Cells, Apoptosis and Autophagy. Our department has laboratories and resources located on both the North and South MD Anderson Campuses in Houston, Texas.
The overall goal of our carcinogenesis research is to understand the basic cellular and molecular mechanisms that allow the transformation of normal cells into cancer cells. Defining these mechanisms will help identify new cancer targets and novel strategies for identifying, treating, and preventing cancer.
Departmental carcinogenesis research includes:
- Discovering new genetic contributors and drivers of cancers
- Identifying genetic and/or therapeutic vulnerabilities in cancers (e.g. synthetic lethality)
- Defining genetic, epigenetic, immunologic, and transcriptional alterations accompanying cancer initiation and progression
- Investigating cell signaling pathways involved in cancer induction and progression
Developing novel computational approaches for cancer research
Enormous amounts of data have been generated from high-throughput, genome-wide experimental approaches, thus creating a pressing need for novel computational approaches to mine and interpret complex "-omics" data sets. Understanding these data sets will help define both the players in biological interaction networks and their functions. Research in the department is combining in-silico approaches with wet-lab experiments to identify drivers and attenuators of cancer. Likewise, the development of CRISPR technology has led to new high-throughput approaches such as genome-wide synthetic lethal screens that also benefit from computational approaches, like those being developed in the department to aid the design and interpretation of high-throughput screens.
Implementing cutting-edge animal models
Our research relies on the development of genetically engineered animal models for investigating the stepwise molecular changes that occur during carcinogenesis, the function of key genes and gene variants in cancer development, and preclinical prevention and therapeutic studies. A number of existing models are being used for these mechanistic studies, including models for skin, mammary gland, prostate, thymus and blood cancers, but we are also creating novel mouse models using modern knockout/knock-in technologies (e.g. CRISPR-Cas9) to study specific genes and pathways involved in cancer induction and progression.
Making discoveries at the intersection of immunology and systems biology
Immunotherapy has been hailed as the fourth pillar of cancer therapy joining surgery, chemotherapy, and radiation treatment. Yet, this treatment approach does not work for all patients. Collaborative departmental research has revealed that patients who respond to immunotherapy have antibody responses against their tumors and that the presence of B cells within a tumor may serve as a marker to predict patient immunotherapy response. These findings are leading to new questions about the role of B cells in immunotherapy response. Other departmental research combining systems-level approaches and wet-lab experiments has revealed that specific mismatch repair-deficient (dMMR) tumors rely on neddylation to remove misfolded or otherwise aberrant proteins, and this mechanism can be exploited by blocking neddylation-mediated protein degradation, which leads to in an increase in immunogenic cell death. These findings suggest that blocking neddylation may benefit patients with dMMR tumors who do not respond to treatment with immunotherapy alone.
Examples of faculty members who are defining the Cellular and Molecular Mechanisms of Carcinogenesis:
C. Marcelo Aldaz - Role of WWOX in cancer and disease; genomic determinants contolling development and progression of pre-invasive breast lesions
Shawn Bratton - Autophagy and prostate cancer; caspase-activating complexes
Sharon Dent - Chromatin remodeling and epigenetics in normal cell growth and in development of cancer and disease
David Johnson - Transcription factor responses in DNA damage and tumor development
Ellen Richie - Regulation of thymus development and homeostasis; role of thymic epithelial cells in regulating T-cell development and T-cell receptor repertoire selection
Kevin McBride - B cell function and antibody repertoire; B cell lymphoma; role of B cells in immunotherapy response
Nidhi Sahni - Systems-level functional and computational genomics, genetic and epigenetic influncing susceptibility and reistance to human cancer and immune system heterogeneity
Margarida Almeida Santos - Tumor promoting roles of genome guardians in leukemia
Richard Wood - Role of DNA polymerase zeta in skin and mammary carcinogenesis
Han Xu - Global view of transcriptional and epigenetic regulation using CRISPR screens; machine-learning and statistical algorithms for high-throughput experiments
Epigenetic factors that regulate DNA methylation, histone modification and chromatin organization can act as either oncogenes or tumor suppressors. Departmental epigenetics research seeks to define both the normal functions of these factors as well as their roles in cancer formation or suppression.
Readers, Writers and Erasers of Epigenetic Marks
Epigenetic marks include cytosine methylation and hydroxymethylation of DNA and methylation, acetylation, phosphorylation, and ubiquitination of histones. These marks are created by enzymes called "writers." Epigenetic "readers" are effector proteins that bear domains that recognize the specific marks left by the "writers," and epigenetic "erasers" can remove these marks. Thus, multiple epigenomes can be created from a single genome.
Uncovering how epigenetic changes and mutations in epigenetic proteins alter gene expression
The major outcome of epigenetic change is alterations in gene expression. Some epigenetic changes are required for normal development and stem cell differentiation, whereas others are aberrant and can lead to diseases, including immunodeficiency, centromeric region instability and facial anomalies syndrome (ICF) and leukemia and other cancers. Importantly, many epigenetic proteins are mutated in human disease, and epigenetic alterations may be just as important as DNA mutations in driving cancer. In addition to controlling gene transcription, these chromatin-modifying enzymes regulate other processes that require access to DNA, including DNA replication and repair.
Departmental epigenetic research areas include:
- Uncovering epigenetic factors controlling developmental reprogramming
- Discovering biological roles of histone lysine and arginine methylation
- Defining the structure and function of epigenetic proteins and epigenetic marks
- Revealing the cellular functions of ATP-dependent chromatin remodelers
- Identifiying and characterizing “readers” of epigenetic marks
- Understanding the role of histone modifications in DNA repair
- Deciphering crosstalk between: histone modifications; histone modifications and DNA methylation; and histone modifications and post-translational modifications of non-histone substrates
Epigenetics-based research provides new avenues for cancer treatment
Epimutations, unlike genetic mutations, can be reversed by chemotherapeutic intervention, which makes epigenetic therapy conceptually appealing. Researchers in the department are screening and identifying small-molecule regulators of epigenetic modifiers and evaluating their potential as anti-cancer drugs, providing clear translational relevance to this research.
As an example, mutliple departmental research teams combined their expertise to use cell culture experiments, computational approaches evaluating cancer cell line RNAi screens, and animal xenograft models to show that small molecule inhibition of an arginine methyltransferase (CARM1) in CREBBP/EP300-mutated diffuse large B-cell lymphomas (DLBCLs) reduces histone acetyltransferase activity and causes synthetic lethality through downregulation of CBP-target genes. This synthetic interaction reveals the possibility that combination therapy using CARM1 inhibitors with CBP/p300 inhibitors may be useful for treating DLBCLs and other cancers with non-mutated CREBBP/EP300.
Examples of faculty engaged in epigenetics research:
Blaine Bartholomew - ATP-dependent chromatin remodelers influence on chromatin dynamics and non-coding RNA transcription
Mark Bedford - Arginine methylation in cellular processes; development of technologies to identify readers of proteins bearing specific epigenetic marks
Taiping Chen - Biological function of histone methylases and demethylases in development and disease
Xiaodong Cheng - Structure and function of readers, writers, and erasers of DNA modifications and their associated histone modifications
Sharon Dent - Histone modifying proteins in development and disease
David Johnson - Recruitment of histone modifying enzymes by E2F1
Margarida Almeida Santos - Epigenetic regulators affecting hematopoietic stem cells
Understanding the mechanisms that damage and repair DNA is fundamental to cancer research
DNA breaks can result from molecularly programmed, intentional DNA damage or non-programmed, incidental DNA damage. Intentional breaks results from specialized cellular processes such as those needed for accurate segregation of chromosomes during meiosis and for creating immune system diversity. In contrast, incidental DNA damage results from exposure to DNA damaging agents from both external and internal sources. External sources include ultraviolet radiation from the sun and chemicals in the environment. Internal sources include reactive chemical species, such as oxygen and water as well as accidental DNA breaks formed during DNA replicaiton. Moreover, many cancer therapies induce irreparable DNA damage leading to cell death. Therefore, investigating how cells respond to and repair DNA damage is important for understanding the causes of cancer and developing new treatments. Research in this area employs a broad range of approaches including studies using protein biochemistry, single-cell genomics, high-resolution microscopy, and genetically engineered mouse models.
Departmental research related to genomic stability includes:
- Defining molecular mechanisms of DNA double-strand break repair
- Discovering new DNA repair pathways and proteins
- Defining the functions of DNA polymerases in DNA repair
- Characterizing DNA damage and repair processes in normal cell function and in carcinogenesis
- Learning how DNA damage and repair contribute to immune system diversity
- Unraveling the relationships between DNA damage, chromatin remodeling, and DNA repair
When DNA damage causes cells to go awry
Department investigators are studying the protein machinery involved in several DNA repair pathways, including homologous recombination and DNA end-joining proccesses for the repair of DNA double-strand breaks, and nucleotide excision repair for the repair of ultraviolet radiation-induced DNA damage and other strand-distorting lesions.
Faculty are also uncovering how programmed DNA damage and repair are involved in normal cellular processes, such as meiosis and immune system B cell development, as well as how these normal processes go awry and contribute to cancer and disease.
Other active areas of research include investigations into the actions of DNA polymerases at repair sites, how chromatin-modifying proteins cooperate with the DNA repair machinery to facilitate repair in the context of chromatin, the mechanisms underlying the conversion of DNA damage into the mutations that cause cancer, and the mechanisms that allow cells to tolerate and survive DNA damage.
Examples of faculty members leading the way in DNA Replication, Recombination, and Repair :
Francesca Cole - DSB repair by homologous recombination
David Johnson - Role of E2F1 in DNA damage repair
Kevin McBride - Role of programmed DNA damage in creating antibody diversity and leading to lymphomagenesis
Margarida Almeida Santos - DNA damage-induced differentiation of stem-like cancer cells
Richard Wood - Nucleotide excision repair, DNA crosslink repair, role of polymerases in DNA damage tolerance
Stem cells are undifferentiated cells that are unique in their ability to self-renew to create more stem cells while also being able to create daughter cells that can differentiate into other cell types. Most, if not all, cancerous states reflect inappropriate or incomplete cellular differentiation. Aggressive, therapy resistant cancer cells often resemble stem cells in terms of their transcription profiles and self-renewal capacities. Likewise, unregulated growth, abnormal cell division, and defective apoptotic cell death pathways are hallmark features of tumors.
The goal of research in this area is to define normal stem cell biology and developmental pathways as well as to define genetic, molecular, and biochemical mechanisms that regulate cell proliferation, apoptosis and autophagy and relate these pathways to carcinogenesis.
Specific research in this area includes:
- Defining pathways that govern stem cell biology and embryo development
- Understanding DNA damage response in cancer stem cells
- Epigenetic modifications in embyronic, adult, and cancer stem cells
- Epigenetic mechanisms in early embryos and germ cells
- Role of caspases in apoptosis
- Apoptosis and autophagy in normal and disease processes
Using stem cells to learn about cancer
Our research using mouse embryonic and adult stem cells has led to several foundational discoveries. For example, research centered on GCN5, a histone acetyltransferase component of the SAGA complex, uncovered a Myc-SAGA axis that is critical for driving stem cells to pluripotency and is essential for the expression of cell-cycle genes driven by MYC overexpression in a mouse model of B cell lymphoma. Studies of SETDB1, a lysine methyltransferase that deposits the repressive H3K9me3 mark, revealed that SETDB1-dependent gene repression is essential for preserving intestinal stem cell identity by modulating the Wnt and Notch signaling pathways. Other research using mouse models of MLL-rearranged acute myeloid leukemia showed that protein arginine methyltransferase 5 (PRMT5) is essential for the initiation and maintenance of MLL-AF9-mediated leukemia and that inhibiting PRMT5 restores normal differentiation to hematopoietic stem cells.
Apoptosis and autophagy: cancer inhibitors and facilitators
Autophagy (self-cannibalism) and apoptosis (programmed cell death) are fundamental cellular processes that provide mechanisms for cell survival (autophagy) and cell death (apoptosis). Autophagy provides cells with means not only to survive cellular stress and to recycle cellular materials and organelles but also to rid themselves of damaged, malformed, or foreign material. Although autophagy helps suppress carcinogenesis, it can also promote tumor progression, metastasis, and cancer therapy resistance. Apoptosis is required for normal organismal development, but also provides a mechanism to stop cells with DNA damage from dividing. Many chemotherapeutics work by causing DNA damage and inducing apoptosis; however, defects in apoptosis contribute to both tumorigenesis and resistance to cancer treatment. Therefore, defining the molecular mechanisms guiding autophagy and apoptosis, and the pathways allowing cross-talk between them, will provide insights into how cells evade and succumb to cancer treatments.
Faculty with research interests in Cancer Stem Cells and Programmed Cell Death:
Blaine Bartholomew - Chromatin remodelers in pluripotency and development
Shawn Bratton - Heat shock- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- induced apoptosis; caspase-activating complexes and the apoptosome; structure and function of autophagosomes; role of autophagy in prostate cancer
Taiping Chen - Epigenetic regulation of embryonic and adult stem cell behavior and function
Sharon Dent - Chromatin modifiers in embryonic stem cells and somatic cell reprogramming
Margarida Almeida Santos - Epigenetic regulation of cancer stem cells
Basu S, Dong Y, Kumar R, Jeter C, Tang DG. Slow-cycling (dormant) cancer cells in therapy resistance, cancer relapse and metastasis. Semin Cancer Biol. 2021 May 9:S1044-579X(21)00122-X. doi: 10.1016/j.semcancer.2021.04.021. Online ahead of print.
Chen J, Horton J, Sagum C, Zhou J, Cheng X, Bedford MT. Histone H3 N-terminal mimicry drives a novel network of methyl-effector interactions. Biochem J. 2021 May 10:BCJ20210203. doi: 10.1042/BCJ20210203. Online ahead of print.
Genois MM, Gagné JP, Yasuhara T, Jackson J, Saxena S, Langelier MF, Ahel I, Bedford MT, Pascal JM, Vindigni A, Poirier GG, Zou L. CARM1 regulates replication fork speed and stress response by stimulating PARP1. Mol Cell. 2021 Feb 18;81(4):784-800.e8
Guo L, Li Y, Cirillo KM, Marick RA, Su Z, Yin X, Hua X, Mills GB, Sahni N*, Yi SS*. mi-IsoNet: systems-scale microRNA landscape reveals rampant isoform-mediated gain of target interaction diversity and signaling specificity. Brief Bioinform. 2021 Apr 14:bbab091. doi: 10.1093/bib/bbab091. Online ahead of print. (*co-corresponding authors)
Hu X, Estecio MR, Chen R, Reuben A, Wang L, Fujimoto J, Carrot-Zhang J, McGranahan N, Ying L, Fukuoka J, Chow CW, Pham HHN, Godoy MCB, Carter BW, Behrens C, Zhang J, Antonoff MB, Sepesi B, Lu Y, Pass HI, Kadara H, Scheet P, Vaporciyan AA, Heymach JV, Wistuba II, Lee JJ, Futreal PA, Su D, Issa JJ, Zhang J. Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas. Nat Commun. 2021 Jan 29;12(1):687.
Jung YS, Stratton SA, Lee SH, Kim MJ, Jun S, Zhang J, Zheng B, Cervantes CL, Cha JH, Barton MC, Park JI. TMEM9-v-ATPase Activates Wnt/β-Catenin Signaling via APC Lysosomal Degradation for Liver Regeneration and Tumorigenesis. Hepatology. 2021 Feb;73(2):776-794.
Koutelou E, Farria AT, Dent SYR. Complex functions of Gcn5 and Pcaf in development and disease. Biochim Biophys Acta Gene Regul Mech. 2021 Feb;1864(2):194609.
Li Y, Burgman B, Khatri IS, Pentaparthi SR, Su Z, McGrail DJ, Li Y, Wu E, Eckhardt SG, Sahni N*, Yi SS. e-MutPath: computational modeling reveals the functional landscape of genetic mutations rewiring interactome networks. Nucleic Acids Res. 2021 Jan 11;49(1):e2 (*co-corresponding author)
Martin SK, Tomida J, Wood RD. Disruption of DNA polymerase ζ engages an innate immune response. Cell Rep. 2021 Feb 23;34(8):108775.
Srinivasan J, Lancaster JN, Singarapu N, Hale LP, Ehrlich LIR, Richie ER. Age-Related Changes in Thymic Central Tolerance. Front Immunol. 2021 Apr 22;12:676236. (Review)
Toraason E, Horacek A, Clark C, Glover ML, Adler VL, Premkumar T, Salagean A, Cole F, Libuda DE. Meiotic DNA break repair can utilize homolog-independent chromatid templates in C. elegans. Curr Biol. 2021 Apr 12;31(7):1508-1514.e5.
Trinh A, Gil Del Alcazar CR, Shukla SA, Chin K, Chang YH, Thibault G, Eng J, Jovanović B, Aldaz CM, Park SY, Jeong J, Wu C, Gray J, Polyak K. Genomic Alterations during the In Situ to Invasive Ductal Breast Carcinoma Transition Shaped by the Immune System. Mol Cancer Res. 2021 Apr;19(4):623-635.
Wright T, Wang Y, Bedford MT. The Role of the PRMT5-SND1 Axis in Hepatocellular Carcinoma. Epigenomes. 2021 Mar;5(1):2. (Review)
Yang J, Horton JR, Akdemir KC, Li J, Huang Y, Kumar J, Blumenthal RM, Zhang X, Cheng X. Preferential CEBP binding to T:G mismatches and increased C-to-T human somatic mutations. Nucleic Acids Res. 2021 Apr 20:gkab276. doi: 10.1093/nar/gkab276. Online ahead of print.
Zahn KE, Jensen RB, Wood RD, Doublié S. Human DNA polymerase θ harbors DNA end-trimming activity critical for DNA repair. Mol Cell. 2021 Apr 1;81(7):1534-1547.e4.
Abba MC, Canzoneri R, Gurruchaga A, Lee J, Tatineni P, Kil H, Lacunza E, Aldaz CM. LINC00885 a Novel Oncogenic Long Non-Coding RNA Associated with Early Stage Breast Cancer Progression. Int J Mol Sci. 2020 Oct 8;21(19):7407.
Benavides F, Rülicke T, Prins JB, Bussell J, Scavizzi F, Cinelli P, Herault Y, Wedekind D. Genetic quality assurance and genetic monitoring of laboratory mice and rats: FELASA Working Group Report. Lab Anim. 2020 Apr;54(2):135-148.
Bhardwaj SK, Hailu SG, Olufemi L, Brahma S, Kundu S, Hota SK, Persinger J, Bartholomew B. Dinucleosome specificity and allosteric switch of the ISW1a ATP-dependent chromatin remodeler in transcription regulation. Nat Commun. 2020 Nov 20;11(1):5913.
Farria AT, Plummer JB, Salinger AP, Shen J, Lin K, Lu Y, McBride KM, Koutelou E, Dent SYR. Transcriptional Activation of MYC-Induced Genes by GCN5 Promotes B-cell Lymphomagenesis. Cancer Res. 2020 Dec 15;80(24):5543-5553.
Hardikar S, Ying Z, Zeng Y, Zhao H, Liu B, Veland N, McBride K, Cheng X, Chen T. The ZBTB24-CDCA7 axis regulates HELLS enrichment at centromeric satellite repeats to facilitate DNA methylation. Protein Cell. 2020 Mar;11(3):214-218.
Helmink BA, Reddy SM, Gao J, Zhang S, Basar R, Thakur R, Yizhak K, Sade-Feldman M, Blando J, Han G, Gopalakrishnan V, Xi Y, Zhao H, Amaria RN, Tawbi HA, Cogdill AP, Liu W, LeBleu VS, Kugeratski FG, Patel S, Davies MA, Hwu P, Lee JE, Gershenwald JE, Lucci A, Arora R, Woodman S, Keung EZ, Gaudreau PO, Reuben A, Spencer CN, Burton EM, Haydu LE, Lazar AJ, Zapassodi R, Hudgens CW, Ledesma DA, Ong S, Bailey M, Warren S, Rao D, Krijgsman O, Rozeman EA, Peeper D, Blank CU, Schumacher TN, Butterfield LH, Zelazowska MA, McBride KM, Kalluri R, Allison J, Petitprez F, Fridman WH, Sautès-Fridman C, Hacohen N, Rezvani K, Sharma P, Tetzlaff MT, Wang L, Wargo JA. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020 Jan;577(7791):549-555.
Hwang T, Reh S, Dunbayev Y, Zhong Y, Takata Y, Shen J, McBride KM, Murnane JP, Bhak J, Lee S, Wood RD, Takata KI. Defining the mutation signatures of DNA polymerase θ in cancer genomes. NAR Cancer. 2020 Sep;2(3):zcaa017.
Jain K, Fraser CS, Marunde MR, Parker MM, Sagum C, Burg JM, Hall N, Popova IK, Rodriguez KL, Vaidya A, Krajewski K, Keogh MC, Bedford MT*, Strahl BD.* Characterization of the plant homeodomain (PHD) reader family for their histone tail interactions. Epigenetics Chromatin. 2020 Jan 24;13(1):3 (*Co-corresponding authors)
Kumar A, Zhong Y, Albrecht A, Sang PB, Maples A, Liu Z, Vinayachandran V, Reja R, Lee CF, Kumar A, Chen J, Xiao J, Park B, Shen J, Liu B, Person MD, Trybus KM, Zhang KYJ, Pugh BF, Kamm KE, Milewicz DM, Shen X*, Kapoor P*. Actin R256 Mono-methylation Is a Conserved Post-translational Modification Involved in Transcription. Cell Rep. 2020 Sep 29;32(13):108172. (*co-corresponding authors)
Kumar J, Kaur G, Ren R, Lu Y, Lin K, Li J, Huang Y, Patel A, Barton MC, Macfarlan T, Zhang X, Cheng X. KRAB domain of ZFP568 disrupts TRIM28-mediated abnormal interactions in cancer cells. NAR Cancer. 2020 Jun;2(2):zcaa007.
McGrail DJ, Garnett J, Yin J, Dai H, Shih DJH, Lam TNA, Li Y, Sun C, Li Y, Schmandt R, Wu JY, Hu L, Liang Y, Peng G, Jonasch E, Menter D, Yates MS, Kopetz S, Lu KH, Broaddus R, Mills GB, Sahni N,* Lin SY.* Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer. Cancer Cell. 2020 Mar 16;37(3):371-386.e12. (*Co-corresponding authors)
Shen Y, Gao G, Yu X, Kim H, Wang L, Xie L, Schwarz M, Chen X, Guccione E, Liu J*, Bedford MT*, Jin J*. Discovery of First-in-Class Protein Arginine Methyltransferase 5 (PRMT5) Degraders. J Med Chem. 2020 Sep 10;63(17):9977-9989. (*Co-corresponding authors)
Turner OC, Aeffner F, Bangari DS, High W, Knight B, Forest T, Cossic B, Himmel LE, Rudmann DG, Bawa B, Muthuswamy A, Aina OH, Edmondson EF, Saravanan C, Brown DL, Sing T, Sebastian MM. Society of Toxicologic Pathology Digital Pathology and Image Analysis Special Interest Group Article*: Opinion on the Application of Artificial Intelligence and Machine Learning to Digital Toxicologic Pathology. Toxicol Pathol. 2020 Feb;48(2):277-294.
Veazey KJ, Cheng D, Lin K, Villarreal OD, Gao G, Perez-Oquendo M, Van HT, Stratton SA, Green M, Xu H, Lu Y, Bedford MT, Santos MA. CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas. Leukemia. 2020 Jun 24. doi: 10.1038/s41375-020-0908-8.
Woodcock CB, Horton JR, Zhou J, Bedford MT, Blumenthal RM, Zhang X, Cheng X. Biochemical and structural basis for YTH domain of human YTHDC1 binding to methylated adenine in DNA. Nucleic Acids Res. 2020 Oct 9;48(18):10329-10341.
Zelazowska MA, Dong Q, Plummer JB, Zhong Y, Liu B, Krug LT, McBride KM. Gammaherpesvirus-infected germinal center cells express a distinct immunoglobulin repertoire. Life Sci Alliance. 2020 Feb 6;3(3):e201900526.
Zeng Y*, Ren R*, Kaur G, Hardikar S, Ying Z, Babcock L, Gupta E, Zhang X, Chen T#, Cheng X#. The inactive Dnmt3b3 isoform preferentially enhances Dnmt3b-mediated DNA methylation. Genes Dev. 2020 Oct 1;34(21-22):1546-58. (*co-first authors, #co-corresponding authors)
Bao J, Di Lorenzo A, Lin K, Lu Y, Zhong Y, Sebastian MM, Muller WJ, Yang Y, Bedford MT. (2019) Mouse models of overexpression reveal distinct oncogenic roles for different type I protein arginine methyltransferases. Cancer Res. 79(1):21-32.
Gao G, Zhang L, Villarreal OD, He W, Su D, Bedford E, Moh P, Shen J, Shi X, Bedford MT, Xu H. (2019) PRMT1 loss sensitizes cells to PRMT5 inhibition. Nucleic Acids Res. 47(10):5038-5048.
He W, Zhang L, Villarreal OD, Fu R, Bedford E, Dou J, Patel AY, Bedford MT, Shi X, Chen T, Bartholomew B, Xu H. (2019) De novo identification of essential protein domains from CRISPR-Cas9 tiling-sgRNA knockout screens. Nat Commun. 10(1):4541.
Hussain T, Kil H, Hattiangady B, Lee J, Kodali M, Shuai B, Attaluri S, Takata Y, Shen J, Abba MC, Shetty AK, Aldaz CM. (2019) Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus. Neurobiol Dis. 121:163-176.
Koutelou E, Wang L, Schibler A, Chao HP, Kuang X, Lin K, Lu Y, Shen J, Jeter CR, Salinger A, Wilson M, Chen YC, Atanassov BS, Tang DG, Dent SY. (2019) Usp22 controls multiple signaling pathways that are essential for vasculature formation in the mouse placenta. Development. Feb 22;146(4). pii: dev174037. ]
Manickavinayaham S, Vélez-Cruz R, Biswas AK, Bedford E, Klein BJ, Kutateladze TG, Liu B, Bedford MT, Johnson DG. (2019) E2F1 acetylation directs p300/CBP-mediated histone acetylation at DNA double-strand breaks to facilitate repair. Nat Commun. 10(1):4951.
McBride KM, Kil H, Mu Y, Plummer JB, Lee J, Zelazowski MJ, Sebastian M, Abba MC, Aldaz CM. (2019) Wwox Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies. Front Oncol. 9:517.
Patel L, Kang R, Rosenberg SC, Qiu Y, Raviram R, Chee S, Hu R, Ren B, Cole F,* Corbett KD*. (2019) Dynamic reorganization of the genome shapes the recombination landscape in meiotic prophase. Nat Struct Mol Biol. 26(3):164-174. (*co-corresponding authors)
Ren R, Hardikar S, Horton JR, Lu Y, Zeng Y, Singh AK, Lin K, Coletta LD, Shen J, Lin Kong CS, Hashimoto H, Zhang X, Chen T, Cheng X. (2019) Structural basis of specific DNA binding by the transcription factor ZBTB24. Nucleic Acids Res. 47(16):8388-8398.
Wible DJ, Chao HP, Tang DG, Bratton SB. (2019) ATG5 cancer mutations and alternative mRNA splicing reveal a conjugation switch that regulates ATG12-ATG5-ATG16L1 complex assembly and autophagy. Cell Discov. 5:42.
Veland N, Lu Y, Hardikar S, Gaddis S, Zeng Y, Liu B, Estecio MR, Takata Y, Lin K, Tomida MW, Shen J, Saha D, Gowher H, Zhao H, Chen T. (2019) DNMT3L facilitates DNA methylation partly by maintaining DNMT3A stability in mouse embryonic stem cells. Nucleic Acids Res. 47(1):152-167.
Appikonda S, Thakkar KN, Shah PK, Dent SYR, Andersen JN, Barton MC. (2018) Cross-talk between chromatin acetylation and SUMOylation of tripartite motif-containing protein 24 (TRIM24) impacts cell adhesion. J Biol Chem. 293(19):7476-7485.
Bao J, Perez CJ, Kim J, Zhang H, Murphy CJ, Hamidi T, Jaubert J, Platt CD, Chou J, Deng M, Zhou MH, Huang Y, Gaitán-Peñas H, Guénet JL, Lin K, Lu Y, Chen T, Bedford MT, Dent SY, Richburg JH, Estévez R, Pan HL, Geha RS, Shi Q, Benavides F. (2018) Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice. JCI Insight. 3(16):e99767.
Bao J, Rousseaux S, Shen J, Lin K, Lu Y, Bedford MT. The arginine methyltransferase CARM1 represses p300•ACT•CREMτ activity and is required for spermiogenesis. (2018) Nucleic Acids Res. 46(9):4327-4343.
Brahma S, Ngubo M, Paul S, Udugama M, Bartholomew B. (2018) The Arp8 and Arp4 module acts as a DNA sensor controlling INO80 chromatin remodeling. Nat Commun. 90(1):3309
Cheng D, Vemulapalli V, Lu Y, Shen J, Aoyagi S, Fry CJ, Yang Y, Foulds CE, Stossi F, Treviño LS, Mancini MA, O’Malley BW, Walker CL, Boyer TG, Bedford MT. (2018) CARM1 methylates MED12 to regulate its RNA binding ability. Life Sci Alliance. 1(5):e201800117.
Das P, Veazey KJ, Van HT, Kaushik S, Lin K, Lu Y, Ishii M, Kikuta J, Ge K, Nussenzweig A, Santos MA. (2018) Histone methylation regulator PTIP is required to maintain normal and leukemic bone marrow niches. Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):E10137-E10146. pii: 201806019.
Franco HL, Nagari A, Malladi V, Li W, Xi Y, Richardson D, Allton KL, Tanaka K, Li J, Murakami S, Keyomarsi K, Bedford MT, Shi X, Li W, Barton MC, Dent SYR, Kraus WL. (2018) Enhancer transcription reveals subtype-specific gene expression programs controlling breast cancer pathogenesis. Genome Res. 28(2):159-170.
Hamidi T, Singh AK, Veland N, Vemulapalli V, Chen J, Hardikar S, Bao J, Fry CJ, Yang V, Lee KA, Guo A, Arrowsmith CH, Bedford MT, Chen T. (2018) Identification of Rpl29 as a major substrate of the lysine methyltransferase Set7/9. J Biol Chem. 293(33):12770-12780.
Jain AK, Barton MC. (2018) p53: emerging roles in stem cells, development and beyond. Development. 145(8): dev158360.
Kaushik S, Liu F, Veazey KJ, Gao G, Das P, Neves LF, Lin K, Zhong Y, Lu Y, Giuliani V, Bedford MT, Nimer SD, Santos MA. (2018) Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. Leukemia. 32(2):499-509.
Kang R, Zelazowski MJ, Cole F. (2018) Missing the Mark: PRDM9-dependent methylation is required for meiotic DSB targeting. Mol Cell. 69(5):725-727.
Singarapu N, Ma K, Reeh KAG, Shen J, Lancaster JN, Yi S, Xie H, Orkin SH, Manley NR, Ehrlich LIR, Jiang N, Richie ER. (2018) Polycomb repressive complex 2 is essential for development and maintenance of a functional TEC compartment. Sci Rep. 8(1):14335.
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