Scholars@Duke
G. Greg Wang

G. Greg Wang

Professor of Pharmacology and Cancer Biology
Pharmacology & Cancer Biology
greg.wang@duke.edu
3 Genome Court, Box 103057, Durham, NC 27710
MSRB3, 3 Genome Court, Durham, NC 27710

Selected Publications

The sotos syndrome gene Nsd1 safeguards developmental gene enhancers poised for transcription by maintaining the precise deposition of histone methylation.

Journal Article J Biol Chem · March 19, 2025 Germline haploinsufficiency of NSD1 is implicated as the etiology of Sotos syndrome; however, the underlying mechanism remains far from being clear. Here, we use mouse embryonic stem cell (mESC) differentiation as a model system to address this question. W ... Full text Link to item Cite

EZH2 PROTACs target EZH2- and FOXM1-associated oncogenic nodes, suppressing breast cancer cell growth.

Journal Article Oncogene · August 2024 Breast cancer (BC) remains the second leading cause of cancer-related mortalities in women. Resistance to hormone therapies such as tamoxifen, an estrogen receptor (ER) inhibitor, is a major hurdle in the treatment of BC. Enhancer of zeste homolog 2 (EZH2) ... Full text Link to item Cite

Structural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction.

Journal Article Nat Commun · July 23, 2024 Isoform 1 of DNA methyltransferase DNMT3A (DNMT3A1) specifically recognizes nucleosome monoubiquitylated at histone H2A lysine-119 (H2AK119ub1) for establishment of DNA methylation. Mis-regulation of this process may cause aberrant DNA methylation and path ... Full text Link to item Cite

TAF2, within the TFIID complex, regulates the expression of a subset of protein-coding genes.

Journal Article Cell Death Discov · May 21, 2024 TFIID, one of the general transcription factor (GTF), regulates transcriptional initiation of protein-coding genes through direct binding to promoter elements and subsequent recruitment of other GTFs and RNA polymerase II. Although generally required for m ... Full text Link to item Cite

Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations.

Journal Article Nat Commun · April 10, 2024 DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA me ... Full text Link to item Cite

Through the lens of phase separation: intrinsically unstructured protein and chromatin looping.

Journal Article Nucleus · December 2023 The establishment, maintenance and dynamic regulation of three-dimensional (3D) chromatin structures provide an important means for partitioning of genome into functionally distinctive domains, which helps to define specialized gene expression programs ass ... Full text Open Access Link to item Cite

Onco-condensates: formation, multi-component organization, and biological functions.

Journal Article Trends Cancer · September 2023 Numerous cellular processes occur in the context of condensates, a type of large, membrane-less biomolecular assembly generated through phase separation. These condensates function as a hub of diversified cellular events by concentrating the required compo ... Full text Link to item Cite

Charles David Allis (1951-2023).

Journal Article Nat Genet · April 2023 Full text Link to item Cite

Dissecting and targeting noncanonical functions of EZH2 in multiple myeloma via an EZH2 degrader.

Journal Article Oncogene · March 2023 Multiple myeloma (MM) is the second most common hematological malignancy with poor prognosis. Enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27 ... Full text Link to item Cite

Ribosomal protein RPL11 haploinsufficiency causes anemia in mice via activation of the RP-MDM2-p53 pathway.

Journal Article J Biol Chem · January 2023 Recent discovery of the ribosomal protein (RP) RPL11 interacting with and inhibiting the E3 ubiquitin ligase function of MDM2 established the RP-MDM2-p53 signaling pathway, which is linked to biological events, including ribosomal biogenesis, nutrient avai ... Full text Link to item Cite

A cryptic transactivation domain of EZH2 binds AR and AR's splice variant, promoting oncogene activation and tumorous transformation.

Journal Article Nucleic Acids Res · October 28, 2022 Enhancer of Zeste Homolog 2 (EZH2) and androgen receptor (AR) are crucial chromatin/gene regulators involved in the development and/or progression of prostate cancer, including advanced castration-resistant prostate cancer (CRPC). To sustain prostate tumor ... Full text Open Access Link to item Cite

DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T cells in PTCL-NOS.

Journal Article Blood · September 15, 2022 Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma ... Full text Link to item Cite

Discovery of a First-in-Class Degrader for Nuclear Receptor Binding SET Domain Protein 2 (NSD2) and Ikaros/Aiolos.

Journal Article J Med Chem · August 11, 2022 Overexpression of nuclear receptor binding SET domain protein 2 (NSD2) is frequent in multiple myeloma (MM). However, existing NSD2 inhibitors are largely ineffective in suppressing MM cell proliferation. Here, we report the discovery of a first-in-class N ... Full text Link to item Cite

Structure of DNMT3B homo-oligomer reveals vulnerability to impairment by ICF mutations.

Journal Article Nat Commun · July 22, 2022 DNA methyltransferase DNMT3B plays an essential role in establishment of DNA methylation during embryogenesis. Mutations of DNMT3B are associated with human diseases, notably the immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome ... Full text Link to item Cite

Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic.

Journal Article Oncogene · June 2022 WD repeat domain 5 (WDR5), an integral component of the MLL/KMT2A lysine methyltransferase complex, is critically involved in oncogenesis and represents an attractive onco-target. Inhibitors targeting protein-protein interactions (PPIs) between WDR5 and it ... Full text Link to item Cite

Oncogenic fusion proteins and their role in three-dimensional chromatin structure, phase separation, and cancer.

Journal Article Curr Opin Genet Dev · June 2022 Three-dimensional (3D) chromatin structure plays a critical role in development, gene regulation, and cellular identity. Alterations to this structure can have profound effects on cellular phenotypes and have been associated with a variety of diseases incl ... Full text Link to item Cite

Cell type-specific chromatin topology and gene regulation.

Journal Article Trends Genet · May 2022 Chromatin structure is critically involved in gene regulation and cell fate determination. How this structure is established and maintained in distinct, terminally differentiated cells remains elusive. Winick-Ng et al. address this puzzle by applying immun ... Full text Link to item Cite

Reprogramming CBX8-PRC1 function with a positive allosteric modulator.

Journal Article Cell Chem Biol · April 21, 2022 Canonical targeting of Polycomb repressive complex 1 (PRC1) to repress developmental genes is mediated by cell-type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7, and 8). Based on their central role in silencing and their dysregulation assoc ... Full text Link to item Cite

A NSD3-targeted PROTAC suppresses NSD3 and cMyc oncogenic nodes in cancer cells.

Journal Article Cell Chem Biol · March 17, 2022 Nuclear receptor binding SET domain protein 3 (NSD3), a gene located within the 8p11-p12 amplicon frequently detected in human cancers, encodes a chromatin modulator and an attractive onco-target. However, agents that effectively suppress NSD3-mediated onc ... Full text Link to item Cite

A PRC2-Kdm5b axis sustains tumorigenicity of acute myeloid leukemia.

Journal Article Proc Natl Acad Sci U S A · March 1, 2022 Acute myeloid leukemias (AMLs) with the NUP98-NSD1 or mixed lineage leukemia (MLL) rearrangement (MLL-r) share transcriptomic profiles associated with stemness-related gene signatures and display poor prognosis. The molecular underpinnings of AML aggressiv ... Full text Link to item Cite

EZH2 noncanonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis.

Journal Article Nat Cell Biol · March 2022 Canonically, EZH2 serves as the catalytic subunit of PRC2, which mediates H3K27me3 deposition and transcriptional repression. Here, we report that in acute leukaemias, EZH2 has additional noncanonical functions by binding cMyc at non-PRC2 targets and uses ... Full text Link to item Cite

DOT1L activity in leukemia cells requires interaction with ubiquitylated H2B that promotes productive nucleosome binding.

Journal Article Cell Rep · February 15, 2022 DOT1L methylates histone H3 lysine 79 during transcriptional elongation and is stimulated by ubiquitylation of histone H2B lysine 120 (H2BK120ub) in a classical trans-histone crosstalk pathway. Aberrant genomic localization of DOT1L is implicated in mixed ... Full text Link to item Cite

A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models.

Journal Article Sci Transl Med · September 29, 2021 Interactions between WD40 repeat domain protein 5 (WDR5) and its various partners such as mixed lineage leukemia (MLL) and c-MYC are essential for sustaining oncogenesis in human cancers. However, inhibitors that block protein-protein interactions (PPIs) b ... Full text Link to item Cite

USP7 facilitates SMAD3 autoregulation to repress cancer progression in p53-deficient lung cancer.

Journal Article Cell Death Dis · September 27, 2021 USP7, one of the most abundant ubiquitin-specific proteases (USP), plays multifaceted roles in many cellular events, including oncogenic pathways. Accumulated studies have suggested that USP7, through modulating the MDM2/MDMX-p53 pathway, is a promising ta ... Full text Link to item Cite

Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation.

Journal Article J Am Chem Soc · September 22, 2021 Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited n ... Full text Link to item Cite

Phase separation drives aberrant chromatin looping and cancer development.

Journal Article Nature · July 2021 The development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human haematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) gene ... Full text Link to item Cite

The language of chromatin modification in human cancers.

Journal Article Nat Rev Cancer · July 2021 The genetic information of human cells is stored in the context of chromatin, which is subjected to DNA methylation and various histone modifications. Such a 'language' of chromatin modification constitutes a fundamental means of gene and (epi)genome regul ... Full text Link to item Cite

Polycomb Gene Silencing Mechanisms: PRC2 Chromatin Targeting, H3K27me3 'Readout', and Phase Separation-Based Compaction.

Journal Article Trends Genet · June 2021 Modulation of chromatin structure and/or modification by Polycomb repressive complexes (PRCs) provides an important means to partition the genome into functionally distinct subdomains and to regulate the activity of the underlying genes. Both the enzymatic ... Full text Link to item Cite

Cistrome analysis of YY1 uncovers a regulatory axis of YY1:BRD2/4-PFKP during tumorigenesis of advanced prostate cancer.

Journal Article Nucleic Acids Res · May 21, 2021 Castration-resistant prostate cancer (CRPC) is a terminal disease and the molecular underpinnings of CRPC development need to be better understood in order to improve its treatment. Here, we report that a transcription factor Yin Yang 1 (YY1) is significan ... Full text Open Access Link to item Cite

A conserved BAH module within mammalian BAHD1 connects H3K27me3 to Polycomb gene silencing.

Journal Article Nucleic Acids Res · May 7, 2021 Trimethylation of histone H3 lysine 27 (H3K27me3) is important for gene silencing and imprinting, (epi)genome organization and organismal development. In a prevalent model, the functional readout of H3K27me3 in mammalian cells is achieved through the H3K27 ... Full text Link to item Cite

DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation.

Journal Article Nat Commun · May 3, 2021 DNA methylation and trimethylated histone H4 Lysine 20 (H4K20me3) constitute two important heterochromatin-enriched marks that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two chromati ... Full text Link to item Cite

ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism.

Journal Article Nat Commun · February 16, 2021 Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers pr ... Full text Link to item Cite

R-loop and its functions at the regulatory interfaces between transcription and (epi)genome.

Journal Article Biochim Biophys Acta Gene Regul Mech · 2021 R-loop represents a prevalent and specialized chromatin structure critically involved in a wide range of biological processes. In particular, co-transcriptional R-loops, produced often due to RNA polymerase pausing or RNA biogenesis malfunction, can initia ... Full text Link to item Cite

No Easy Way Out for EZH2: Its Pleiotropic, Noncanonical Effects on Gene Regulation and Cellular Function.

Journal Article Int J Mol Sci · December 14, 2020 Enhancer of zeste homolog 2 (EZH2) plays critical roles in a range of biological processes including organ development and homeostasis, epigenomic and transcriptomic regulation, gene repression and imprinting, and DNA damage repair. A widely known function ... Full text Link to item Cite

BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis.

Journal Article Nat Genet · December 2020 Trimethylated histone H3 lysine 27 (H3K27me3) regulates gene repression, cell-fate determination and differentiation. We report that a conserved bromo-adjacent homology (BAH) module of BAHCC1 (BAHCC1BAH) 'recognizes' H3K27me3 specifically and enforces sile ... Full text Link to item Cite

Epigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion.

Journal Article Cancer Res · November 1, 2020 T-cell exhaustion in cancer is linked to poor clinical outcomes, where evidence suggests T-cell metabolic changes precede functional exhaustion. Direct competition between tumor-infiltrating lymphocytes (TIL) and cancer cells for metabolic resources often ... Full text Link to item Cite

Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation.

Journal Article Proc Natl Acad Sci U S A · August 4, 2020 In mammals, repressive histone modifications such as trimethylation of histone H3 Lys9 (H3K9me3), frequently coexist with DNA methylation, producing a more stable and silenced chromatin state. However, it remains elusive how these epigenetic modifications ... Full text Link to item Cite

Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms.

Journal Article Nat Commun · July 3, 2020 Mammalian DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensi ... Full text Link to item Cite

Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion.

Journal Article Nat Commun · July 3, 2020 Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and is inhibited by small ... Full text Link to item Cite

E2A-PBX1 functions as a coactivator for RUNX1 in acute lymphoblastic leukemia.

Journal Article Blood · July 2, 2020 E2A, a basic helix-loop-helix transcription factor, plays a crucial role in determining tissue-specific cell fate, including differentiation of B-cell lineages. In 5% of childhood acute lymphoblastic leukemia (ALL), the t(1,19) chromosomal translocation sp ... Full text Link to item Cite

Interaction between androgen receptor and coregulator SLIRP is regulated by Ack1 tyrosine kinase and androgen.

Journal Article Sci Rep · December 9, 2019 Aberrant activation of the androgen receptor (AR) may play a critical role in castration resistant prostate cancer. After ligand binding, AR is recruited to the androgen responsive element (ARE) sequences on the DNA where AR interaction with coactivators a ... Full text Link to item Cite

Structure and regulation of ZCCHC4 in m6A-methylation of 28S rRNA.

Journal Article Nat Commun · November 6, 2019 N6-methyladenosine (m6A) modification provides an important epitranscriptomic mechanism that critically regulates RNA metabolism and function. However, how m6A writers attain substrate specificities remains unclear. We report the 3.1 Å-resolution crystal s ... Full text Link to item Cite

Discovery and Characterization of a Cellular Potent Positive Allosteric Modulator of the Polycomb Repressive Complex 1 Chromodomain, CBX7.

Journal Article Cell Chem Biol · October 17, 2019 Polycomb-directed repression of gene expression is frequently misregulated in human diseases. A quantitative and target-specific cellular assay was utilized to discover the first potent positive allosteric modulator (PAM) peptidomimetic, UNC4976, of nuclei ... Full text Link to item Cite

PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation.

Journal Article Blood · October 3, 2019 Dysregulation of polycomb repressive complex 2 (PRC2) promotes oncogenesis partly through its enzymatic function for inducing trimethylation of histone H3 lysine 27 (H3K27me3). However, it remains to be determined how PRC2 activity is regulated in normal a ... Full text Link to item Cite

Understanding histone H3 lysine 36 methylation and its deregulation in disease.

Journal Article Cell Mol Life Sci · August 2019 Methylation of histone H3 lysine 36 (H3K36) plays crucial roles in the partitioning of chromatin to distinctive domains and the regulation of a wide range of biological processes. Trimethylation of H3K36 (H3K36me3) demarcates body regions of the actively t ... Full text Link to item Cite

A Model System for Studying the DNMT3A Hotspot Mutation (DNMT3AR882) Demonstrates a Causal Relationship between Its Dominant-Negative Effect and Leukemogenesis.

Journal Article Cancer Res · July 15, 2019 Mutation of DNA methyltransferase 3A at arginine 882 (DNMT3AR882mut) is prevalent in hematologic cancers and disorders. Recently, DNMT3AR882mut has been shown to have hypomorphic, dominant-negative, and/or gain-of-function effects on DNA methylation under ... Full text Link to item Cite

BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models.

Journal Article Cancer Cell · May 13, 2019 Drug-tolerant "persister" tumor cells underlie emergence of drug-resistant clones and contribute to relapse and disease progression. Here we report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphom ... Full text Link to item Cite

R-loops: formation, function, and relevance to cell stress.

Journal Article Cell Stress · January 21, 2019 Exposure of genomic, single-stranded DNA (ssDNA) during transcription and replication creates opportunities for the formation of inappropriate secondary structures. Cells manage this exposure by using topoisomerases and helicases to reduce the inherent top ... Full text Link to item Cite

ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer.

Journal Article Mol Cell · October 18, 2018 Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR ... Full text Open Access Link to item Cite

The Chromatin Remodeler BPTF Activates a Stemness Gene-Expression Program Essential for the Maintenance of Adult Hematopoietic Stem Cells.

Journal Article Stem Cell Reports · March 13, 2018 Self-renewal and differentiation of adult stem cells are tightly regulated partly through configuration of chromatin structure by chromatin remodelers. Using knockout mice, we here demonstrate that bromodomain PHD finger transcription factor (BPTF), a comp ... Full text Link to item Cite

Structural basis for DNMT3A-mediated de novo DNA methylation.

Journal Article Nature · February 15, 2018 DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) at cytosines is essential for genome regulation and development. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlyi ... Full text Link to item Cite

Pharmacologic Targeting of Chromatin Modulators As Therapeutics of Acute Myeloid Leukemia.

Journal Article Front Oncol · 2017 Acute myeloid leukemia (AML), a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has un ... Full text Link to item Cite

BPTF Is Essential for T Cell Homeostasis and Function.

Journal Article J Immunol · December 1, 2016 Bromodomain PHD finger transcription factor (BPTF), a ubiquitously expressed ATP-dependent chromatin-remodeling factor, is critical for epigenetically regulating DNA accessibility and gene expression. Although BPTF is important for the development of thymo ... Full text Link to item Cite

Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development.

Journal Article Cancer Cell · July 11, 2016 DNA methyltransferase 3A (DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that the DNMT3A mutational hotspot at Arg882 (DNMT3A(R882H)) cooperates with NRAS mutation to tra ... Full text Link to item Cite

Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming.

Journal Article Cell Stem Cell · March 3, 2016 Direct reprogramming of induced cardiomyocytes (iCMs) suffers from low efficiency and requires extensive epigenetic repatterning, although the underlying mechanisms are largely unknown. To address these issues, we screened for epigenetic regulators of iCM ... Full text Link to item Cite

PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease.

Journal Article Cancer Res · February 1, 2016 Overexpression of HOXA/MEIS1/PBX3 homeobox genes is the hallmark of mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML). HOXA9 and MEIS1 are considered to be the most critical targets of MLL fusions and their coexpression rapidly induces A ... Full text Link to item Cite

An Allosteric Interaction Links USP7 to Deubiquitination and Chromatin Targeting of UHRF1.

Journal Article Cell Rep · September 1, 2015 The protein stability and chromatin functions of UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) are regulated in a cell-cycle-dependent manner. We report a structural characterization of the complex between UHRF1 and the deubiquitinase U ... Full text Link to item Cite

Targeting EZH2 and PRC2 dependence as novel anticancer therapy.

Journal Article Exp Hematol · August 2015 Distinctive patterns of chromatin modification control gene expression and define cellular identity during development and cell differentiation. Polycomb repressive complex 2 (PRC2), the sole mammalian enzymatic complex capable of establishing gene-repress ... Full text Link to item Cite

Histone modifications change with age, dietary restriction and rapamycin treatment in mouse brain.

Journal Article Oncotarget · June 30, 2015 The risk of developing neurodegenerative disorders such as Alzheimer's disease (AD) increases dramatically with age. Understanding the underlying mechanisms of brain aging is crucial for developing preventative and/or therapeutic approaches for age-associa ... Full text Link to item Cite

Polycomb genes, miRNA, and their deregulation in B-cell malignancies.

Journal Article Blood · February 19, 2015 Posttranslational modifications of histone proteins represent a fundamental means to define distinctive epigenetic states and regulate gene expression during development and differentiation. Aberrations in various chromatin-modulation pathways are commonly ... Full text Link to item Cite

Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia.

Journal Article Blood · January 8, 2015 Enhancer of zeste homolog 2 (EZH2) and related EZH1 control gene expression and promote tumorigenesis via methylating histone H3 at lysine 27 (H3K27). These methyltransferases are ideal therapeutic targets due to their frequent hyperactive mutations and ov ... Full text Link to item Cite

NUP98-PHF23 is a chromatin-modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD histone reader function.

Journal Article Cancer Discov · May 2014 In this report, we show that expression of a NUP98-PHF23 (NP23) fusion, associated with acute myeloid leukemia (AML) in humans, leads to myeloid, erythroid, T-cell, and B-cell leukemia in mice. The leukemic and preleukemic tissues display a stem cell-like ... Full text Link to item Cite

Tudor: a versatile family of histone methylation 'readers'.

Journal Article Trends Biochem Sci · November 2013 The Tudor domain comprises a family of motifs that mediate protein-protein interactions required for various DNA-templated biological processes. Emerging evidence demonstrates a versatility of the Tudor family domains by identifying their specific interact ... Full text Link to item Cite

An H3K36 methylation-engaging Tudor motif of polycomb-like proteins mediates PRC2 complex targeting.

Journal Article Mol Cell · February 7, 2013 Polycomb repressive complex 2 (PRC2) regulates pluripotency, differentiation, and tumorigenesis through catalysis of histone H3 lysine 27 trimethylation (H3K27me3) on chromatin. However, the mechanisms that underlie PRC2 recruitment and spreading on chroma ... Full text Link to item Cite

An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1.

Journal Article ACS Chem Biol · 2013 EZH2 or EZH1 is the catalytic subunit of the polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). The trimethylation of H3K27 (H3K27me3) is a transcriptionally repressive post-translational modification. Overexpression ... Full text Link to item Cite

Sequence requirements for combinatorial recognition of histone H3 by the MRG15 and Pf1 subunits of the Rpd3S/Sin3S corepressor complex.

Journal Article J Mol Biol · September 28, 2012 The transcriptional output at a genomic locus in eukaryotes is determined, in part, by the pattern of histone modifications that are read and interpreted by key effector proteins. The histone deacetylase activity of the evolutionarily conserved Rpd3S/Sin3S ... Full text Link to item Cite

Covalent histone modifications--miswritten, misinterpreted and mis-erased in human cancers.

Journal Article Nat Rev Cancer · July 2010 Post-translational modification of histones provides an important regulatory platform for processes such as gene transcription and DNA damage repair. It has become increasingly apparent that the misregulation of histone modification, which is caused by the ... Full text Link to item Cite

Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis.

Journal Article Mol Cell · June 25, 2010 MLL1 fusion proteins activate HoxA9 gene expression and cause aggressive leukemias that respond poorly to treatment, but how they recognize and stably bind to HoxA9 is not clearly understood. In a systematic analysis of MLL1 domain recruitment activity, we ... Full text Link to item Cite

Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression.

Journal Article Cell · June 25, 2010 The MLL1 gene is a frequent target for recurrent chromosomal translocations, resulting in transformation of hematopoietic precursors into leukemia stem cells. Here, we report on structure-function studies that elucidate molecular events in MLL1 binding of ... Full text Link to item Cite

Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration.

Journal Article Proc Natl Acad Sci U S A · February 16, 2010 Lens epithelium-derived growth factor (LEDGF) fusion proteins can direct HIV-1 DNA integration to novel sites in the host genome. The C terminus of LEDGF contains an integrase binding domain (IBD), and the N terminus binds chromatin. LEDGF normally directs ... Full text Link to item Cite

Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger.

Journal Article Nature · June 11, 2009 Histone H3 lysine 4 methylation (H3K4me) has been proposed as a critical component in regulating gene expression, epigenetic states, and cellular identities1. The biological meaning of H3K4me is interpreted by conserved modules including plant homeodomain ... Full text Link to item Cite

PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks.

Journal Article Mutat Res · December 1, 2008 Histone covalent modifications regulate many, if not all, DNA-templated processes, including gene expression and DNA damage response. The biological consequences of histone modifications are mediated partially by evolutionarily conserved "reader/effector" ... Full text Link to item Cite

Chromatin remodeling and cancer, Part I: Covalent histone modifications.

Journal Article Trends Mol Med · September 2007 Dynamic chromatin remodeling underlies many, if not all, DNA-templated biological processes, including gene transcription; DNA replication and repair; chromosome condensation; and segregation and apoptosis. Disruption of these processes has been linked to ... Full text Link to item Cite

Chromatin remodeling and cancer, Part II: ATP-dependent chromatin remodeling.

Journal Article Trends Mol Med · September 2007 Connections between perturbations that lie outside of our genome, that is, epigenetic alternations, and tumorigenesis have become increasingly apparent. Dynamic chromatin remodeling of the fundamental nucleosomal structure (covered in this review) or the c ... Full text Link to item Cite

NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis.

Journal Article Nat Cell Biol · July 2007 Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth sy ... Full text Link to item Cite

Survival signaling in HoxA9/Meis1 AML

Journal Article Blood · May 1, 2007 Full text Cite

Persistent transactivation by meis1 replaces hox function in myeloid leukemogenesis models: evidence for co-occupancy of meis1-pbx and hox-pbx complexes on promoters of leukemia-associated genes.

Journal Article Mol Cell Biol · May 2006 Homeobox transcription factors Meis1 and Hoxa9 promote hematopoietic progenitor self-renewal and cooperate to cause acute myeloid leukemia (AML). While Hoxa9 alone blocks the differentiation of nonleukemogenic myeloid cell-committed progenitors, coexpressi ... Full text Link to item Cite

Quantitative production of macrophages or neutrophils ex vivo using conditional Hoxb8.

Journal Article Nat Methods · April 2006 Differentiation mechanisms and inflammatory functions of neutrophils and macrophages are usually studied by genetic and biochemical approaches that require costly breeding and time-consuming purification to obtain phagocytes for functional analysis. Becaus ... Full text Link to item Cite

Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6.

Journal Article Nature · January 12, 2006 Toll-like receptors (TLRs) are activated by pathogen-associated molecular patterns to induce innate immune responses and production of pro-inflammatory cytokines, interferons and anti-inflammatory cytokines. TLRs activate downstream effectors through adapt ... Full text Link to item Cite

Meis1 programs transcription of FLT3 and cancer stem cell character, using a mechanism that requires interaction with Pbx and a novel function of the Meis1 C-terminus.

Journal Article Blood · July 1, 2005 Meis1 is a homeodomain transcription factor coexpressed with Hoxa9 in most human acute myeloid leukemias (AMLs). In mouse models of leukemia produced by Hoxa9, Meis1 accelerates leukemogenesis. Because Hoxa9 immortalizes myeloid progenitors in the absence ... Full text Link to item Cite

Allelic loss and gain, but not genomic instability, as the major somatic mutation in primary hepatocellular carcinoma.

Journal Article Genes Chromosomes Cancer · July 2001 To identify genetic abnormalities in primary hepatocellular carcinoma (HCC), we performed microsatellite analysis (MSA) on 60 Chinese HCC specimens. Utilizing a semi-quantitative MSA and 292 highly polymorphic markers spanning all 22 autosomes, we found th ... Full text Link to item Cite

Genetic aberration in primary hepatocellular carcinoma: correlation between p53 gene mutation and loss-of-heterozygosity on chromosome 16q21-q23 and 9p21-p23.

Journal Article Cell Res · December 2000 To elucidate the molecular pathology underlying the development of hepatocellular carcinoma (HCC), we used 41 highly polymorphic microsatellite markers to examine 55 HCC and corresponding non-tumor liver tissues on chromosome 9, 16 and 17. Loss-of-heterozy ... Full text Link to item Cite