In press – Dr. C. David Allis (Rockefeller University, New York, NY, USA) and colleagues at Tsinghua University (Beijing, China) provide for the first time a general mechanism by which histone marks regulate chromosome compartmentalization by promoting phase separation. They show that heterochromatin protein 1 (HP1) interacts with the histone H3 methyltransferase SUV39H1 and the HP1 scaffolding protein TRIM28 to form complexes with increased multivalent engagement at H3K9me2 and H3K9me3-marked chromatin, and that this leads to structural compartmentalization of heterochromatin. This work was published in Molecular Cell; more here.

October 2018 – Dr. Jonathan Licht (University of Florida Health Cancer Center) and his colleagues at Northwestern University show that a glutamate 76 to lysine mutation in histone H2B is frequent in cancer, particularly in bladder and head and neck cancers. The authors show that this mutation disrupts histones H2B- H4 interaction, reduces nucleosome stability, and increases chromatin opening, leading to gene derepression and neoplastic transformation of human cellular models. This study shows that chromatin structure perturbation, here via histone mutations is causative of cancer. This work was published in Cancer Discovery; more here.

September 2019 – Dr. Keith Robertson (Mayo Clinic, Rochester, MN, USA) uncovered DNA methylation markers that differentiate between localized and advanced-stage papillary renal cell carcinoma. Dr. Robertson and his collaborators (Mayo Clinic, Scottsdale, AZ, USA and Shanghai General Hospital, Shanghai, China) propose the use of these epigenetic markers for the staging and prognosis of papillary renal cell carcinoma. The study was published in Cancer Medicine; more here.

September 2019 – Dr. C. David Allis (Rockefeller University, New York, NY, USA) and colleagues at Columbia University, University of Pennsylvania, McGill University, and Tsinghua University suggested that the DNA methyltransferase DNMT3A and the NSD1 H3K36 dimethyltransferase work together. This was based on the fact that Tatton-Brown-Rahman syndrome (TBRS), a childhood overgrowth disorder characterized by germline mutations in DNMT3A and Sotos syndrome (caused by NSD1 haploinsufficiency) share clinical features. The authors indeed show that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions in euchromatin. Accordingly, blood samples from patients with Sotos syndrome or NSD1-mutant tumors also exhibit hypomethylation of intergenic DNA. This work was published in Nature; more here.

August 2019 – Dr. Owen O’Connor and his colleagues at Columbia University Medical Center conducted a phase I epigenetic combination therapy on patients with peripheral T-cell lymphoma (PTCL). Patients were treated with the hypomethylating agent 5-azacytidine and histone deacetylase inhibitor (HDACi) romidepsin. The authors found the maximum tolerated dose to be 300 mg of 5-azacytidine on days 1-14 and 14 mg/m² of romidepsin on days 8, 15 and 22 on a 35-day cycle without any treatment-related deaths. They authors further found the epigenetic therapy not to be efficacious against non-T-cell lymphoma (complete and overall response in only 5% and 10% of patients, respectively). T-cell lymphoma patients fared better with 55% complete response and 73% overall response rates. This study was published in Blood; ; more here.

July 2019 – Dr. Keith D. Robertson (Mayo Clinic, Rochester, MN, USA) and colleagues at University of Florida and Rutgers University uncovered genomic hypomethylation in Alpha-1 antitrypsin deficiency (AATD) liver disease-impacting genes related to liver cancer, cell cycle, and fibrosis, as well as key regulatory molecules influencing growth, migration, and immune function. They further show that CpG methylation states to be linked to hallmark clinical features of AATD (e.g. hepatocyte degeneration and polymer accumulation) and to sex-specific effects of liver disease progression. This study indicates that 5mC landscapes may be used to stratify patients for liver disease risk and progression. This work was published in Hepatology; more here.

June 2019 – Dr. Raul Urrutia (Medical College of Wisconsin, Milwaukee, WI, USA) and his colleagues showed that S92-phosphorylated heterochromatin protein 1α (HP1α) is catalyzed by Aurora kinase B (AURKB) at early prophase and localizes to centromeres where it contributes to chromosome stability. HP1α mutants that lack phospho-Ser92 lead to mitotic chromosomal instability with anaphase/telophase chromatin bridges and micronuclei. Conversely, HP1α is required for full AURKB activity at the centromere. These findings unveil the critical role of the AURKB and HP1α epigenetic modifiers to genomic stability. The study was published in Cell Cycle; more here.

May 2019 – Dr. Raul Urrutia (Medical College of Wisconsin, Milwaukee, WI, USA) and his colleagues show that epigenetic silencing mediated by H3K9 methylation is essential for both biochemical and biomechanical fibroblast activation, and that targeting this epigenetic pathway may provide therapeutic benefit by returning lung fibroblasts to quiescence to overcome pulmonary fibrosis. Specifically, the authors show that the histone H3K9 methyltransferase G9a (EHMT2) and HP1α are essential to initiation and maintenance of fibroblast activation through epigenetic repression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (PPARGC1A, encoding PGC1α). Inhibition of HP1α/G9a pathway in fibroblasts elevates PGC1α, attenuates TGFβ- and matrix stiffness-promoted H3K9 methylation, and reduces collagen accumulation in the lungs following bleomycin injury. The study was published in JCI Insight; more here.

April 2019 – Dr. C. David Allis and his colleagues (Rockefeller University, New York, NY, USA) found that suppression of cholesterol synthesis with a small molecule drug in both childhood diffuse intrinsic pontine glioma (DIPG) and adult glioma leads to the synthesis of the endogenous liver X receptor ligand 24,25-epoxycholesterol. This in turn leads to cholesterol depletion and glioma cell death. Dr. Allis and coll. also show that the target of the drug is lanosterol synthase, an enzyme of the cholesterol biosynthetic pathway which catalyzes the synthesis of the first sterol used to synthesize cholesterol. This research provides the first evidence that cholesterol control may provide a treatment to the deadly DIPG. The study was published in P.N.A.S. USA; more here.

March 2019 – Dr. Stephan Beck (University College London, London, UK) and his colleagues at TRACERx (TRAcking Cancer Evolution through therapy (Rx)) consortium looked at immune escape during lung cancer progression. They found that sparsely infiltrated tumors show a waning of neoantigen editing during tumor evolution. Immune-infiltrated tumor regions exhibited ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. The authors identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. This study supports a mechanism whereby the immune microenvironment exerts a selective pressure on early-stage non-small-cell lung cancers. This in turn leads to immune evasion, tumor progression, and poor disease-free survival. . This work was published in Nature; more here.

March 2019 – Dr. C. David Allis and his colleagues (Rockefeller University, New York, NY, USA) mapped for the first time more than 4,000 histone missense mutations across 183 different tumor types in more than 3,000 patients. They found oncohistone mutations that circumvent SWI/SNF function in other organisms, as well as those that would disrupt the H2B-H4 interface. Some of these epimutations affect the majority of patients in certain cancers, including diffuse intrinsic pontine gliomas, chondroblastomas, and giant cell tumors of the bone. This work was published in Nature; more here.

March 2019 – Dr. Stephan Beck (University College London, London, UK) and his colleagues studied how lung cancer becomes invasive and turns into full blown squamous cell carcinoma. This work lays down the bases of early lung carcinogenesis and is expected to provide biomarkers for early cancer detection, prognostic factors, and drug targets. The authors showed that progression from lung carcinoma in situ to squamous cell carcinoma is associated with the differential expression of TPM3, PTPRB, SLC34A2, KEAP1, NKX2-1, SMAD4, and SMARCA4, as well as the epigenetic activation of homeobox genes (HOXC8, HOXC9, HOXC10, HOXD10, HOXA11AS) and epigenetic inactivation of NKX2-1. The authors also developed a predictive model for lung cancer progression which should help in treatment management. This work was published in Nature Medicine; more here.

February 2019 – Dr. Keith D. Robertson (Mayo Clinic, Rochester, MN, USA) and colleagues at Rutgers University show the deregulation in hepatocellular carcinoma (HCC) of epigenetic modifiers combined with epigenome loss of 5hmC, locus-specific gains in 5mC and 5hmC, and markedly altered H3K4me1, H3K27ac, H3K4me3, and H3K27me3 histone marks, particularly at enhancers. The study also show that these epigenetic marks collaborate to influence the transcription of genes that regulate HCC proliferation and that hyper-5hmC in HCC-gained active enhancers is linked to elevated gene expression. The authors also show that the epigenetically repressed COMT and FMO3 genes induce apoptosis and decrease cell viability upon reactivation in liver cancer cell lines. This study underscores the importance of DNA and histone epigenetics in HCC tumor pathology; more here.

January 2019 – Dr. Cheryl Arrowsmith (Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada) and colleagues developed a collection of chemical probes to explore the function of protein methyltransferases (PMTs), a major class of epigenetic regulatory enzymes with therapeutic relevance. The authors show the collection of inhibitors and antagonists to modulate most of the key epigenomic regulatory methylation marks on histones H3 and H4. As an example, epigenetic chemical probes in this collection modulate CD4⁺ T cell differentiation, and individual probes alter multiple T cell subpopulations with possible applications in inflammation and immuno-oncology. Using probes, the authors also uncovered a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity. This work was published in Nature Communications.; more here.

September 2018 – Dr. C. David Allis (Rockefeller University, New York, NY, USA), a Member and Officer of the Cancer Epigenetics Society won the prestigious 2018 Albert Lasker Basic Medical Research Award. The Lasker Award website states that it “honors his discoveries on how gene expression is influenced by chemical modification of histones, the proteins that package DNA within chromosomes”. It goes on to say that “C. David Allis uncovered an enzyme that attaches a specific chemical group to a particular amino acid in histones, and this histone-modifying enzyme turned out to be an established gene co-activator whose biochemical capabilities had eluded researchers”. It adds that “Allis unveiled a previously hidden layer of gene control and broke open a new field”. Dr. C. David Allis shares this prestigious award with Michael Grunstein (UCLA, Los Angeles, CA, USA); more here.

September 2018 – Dr. Raul Urrutia (Mayo Clinic, Rochester, MN, USA) and his colleagues at Northwestern University show that inhibitors of bromodomain and extra-terminal (BET) proteins that target BRD4 decrease interferon-γ (IFN-γ)-induced PD-L1 expression in pancreatic stellate cells (PSCs). Activation of PSCs in pancreatic ductal adenocarcinoma (PDAC) leads to fibrosis. The authors further show that interferon regulatory factor 1 (IRF1) mediates IFN-γ-induced PD-L1 expression in PSCs, and that BET inhibitors decrease binding of IRF1 and BRD4 to the PD-L1 promoter, leading to down-regulation of PD-L1. These results indicate the potential use of BET inhibitors in the immunomodulation of PDAC.; more here.