0000000000248824
AUTHOR
Manel Esteller
Release of Hypoacetylated and Trimethylated Histone H4 Is an Epigenetic Marker of Early Apoptosis
11 p.-5 fig.-1 fig. supl.
A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients
Background Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40% approximately. To provide further insight into the prediction of pCR, we evaluated the role of an epigenetic methylation-based signature. Methods Epigenetic assessment of DNA extracted from biopsy archived samples previous to NAC from TNBC patients was performed. Patients included were categorized according to previous response to NAC in responder (pCR or residual cancer burden, RCB = 0) or non-responder (non-pCR or RCB > 0) patients. A methyloma study was performed in a discovery cohort by the Infinium HumanMethylation450 BeadChip (450K arra…
Additional file 2: of A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients
Thirty-five differentially methylated CpGs between responders and non-responders group selected from 450k array (delta value ≥ 0.2) corresponding to 23 genes located in promoter and island/shore (PPT 172 kb)
Additional file 3: of A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients
Eleven differentially methylated CpGs, corresponding to 11 genes, showed significant methylation differences between non-responder and responder patients: 6 genes (LOC641518; LEF1; HOXA5; EVC2; CDKL2; TLX3) presented a methylation increase in non-responders group vs responders, and 5 genes (ZFHX4; LOC100192378; FERD3L; CHL1; TRIP10) decreased methylation level in non-responder patients compared to those who responded to NAC treatment (PPT 225 kb)
Polychlorinated biphenyls affect histone modification pattern in early development of rats: a role for androgen receptor-dependent modulation?
Background: The epigenome represents an important target of environmental pollution. Early-life exposure to polychlorinated biphenyls (PCBs) modifies sex steroid enzymes and receptor transcription patterns. Steroid receptors, such as androgen receptor (AR), function as coregulators of histone modification enzymes. Aim: To clarify if a PCB early-life exposure might affect the epigenome in rat liver, we analyzed some histone post-translational modifications (H3K4me3 and H4K16Ac) and the corresponding histone remodeling enzymes, and the AR as a histone enzyme coregulator. Results: We observed a decrease of H4K16Ac and H3K4me3 levels, possibly linked to the induction of chromatin-modifying enz…
Additional file 1: of A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients
List of all the biological processes enriched for the 71 differentially methylated genes between responder and non-responder patients according to the Gene Ontology analysis (DOCX 32 kb)
Epigenetic differences arise during the lifetime of monozygotic twins.
Monozygous twins share a common genotype. However, most monozygotic twin pairs are not identical; several types of phenotypic discordance may be observed, such as differences in susceptibilities to disease and a wide range of anthropomorphic features. There are several possible explanations for these observations, but one is the existence of epigenetic differences. To address this issue, we examined the global and locus-specific differences in DNA methylation and histone acetylation of a large cohort of monozygotic twins. We found that, although twins are epigenetically indistinguishable during the early years of life, older monozygous twins exhibited remarkable differences in their overall…
DNA methylomes reveal biological networks involved in human eye development, functions and associated disorders
This work provides a comprehensive CpG methylation landscape of the different layers of the human eye that unveils the gene networks associated with their biological functions and how these are disrupted in common visual disorders. Herein, we firstly determined the role of CpG methylation in the regulation of ocular tissue-specification and described hypermethylation of retinal transcription factors (i.e., PAX6, RAX, SIX6) in a tissue-dependent manner. Second, we have characterized the DNA methylome of visual disorders linked to internal and external environmental factors. Main conclusions allow certifying that crucial pathways related to Wnt-MAPK signaling pathways or neuroinflammation are…
Fatty Liver and Fibrosis in Glycine N-Methyltransferase Knockout Mice Is Prevented by Nicotinamide
Deletion of glycine N-methyltransferase (GNMT), the main gene involved in liver S-adenosylmethionine (SAM) catabolism, leads to the hepatic accumulation of this molecule and the development of fatty liver and fibrosis in mice. To demonstrate that the excess of hepatic SAM is the main agent contributing to liver disease in GNMT knockout (KO) mice, we treated 1.5-month-old GNMT-KO mice for 6 weeks with nicotinamide (NAM), a substrate of the enzyme NAM N-methyltransferase. NAM administration markedly reduced hepatic SAM content, prevented DNA hypermethylation, and normalized the expression of critical genes involved in fatty acid metabolism, oxidative stress, inflammation, cell proliferation, …
Gene Amplification-Associated Overexpression of the Selenoprotein tRNA Enzyme TRIT1 Confers Sensitivity to Arsenic Trioxide in Small-Cell Lung Cancer
Simple Summary Small-cell lung cancer accounts for approximately 13% of all new lung cancer diagnoses, but in contrast to non-small-cell lung cancer, the implementation of targeted treatments in small-cell lung cancer has been limited, with little improvement in the clinical outcome in the last several decades. Exploring new pathways for targeted therapy, we have observed that extra-copies of the tRNA modifier TRIT1, involved in the translation of selenoproteins, confers sensitivity to arsenic trioxide in small-cell lung cancer. This finding could open a new therapeutic niche for a tumor type with such a dismal clinical course. The alteration of RNA modification patterns is emerging as a co…
Additional file 5: of A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients
Representation of the pathway interaction network of FERD3L and TRIP10 with other genes using Pathway Commons. FERD3L and TRIP10 are able to interact with different genes that have shown to be implicated in cancer drug resistance (PPT 452 kb)
Additional file 4: of A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients
CpGs studied by pyrosequencing in the DC and in the VC to validate methylation in the candidate genes identified in the 450k array (Illumina). In bold, CpGs from 450k array. Normal type, consecutive CpGs (PPT 140 kb)
Additional file 6: of A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients
Mean differences in methylation levels according to clinicopathological prognostic factors in both cohorts (DC+VC). cT, clinical tumor size; cN, clinical nodule affectation (PPTX 48 kb)
MiR-221 promotes stemness of breast cancer cells by targeting DNMT3b
// Giuseppina Roscigno 1, 2 , Cristina Quintavalle 1, 2 , Elvira Donnarumma 3 , Ilaria Puoti 1 , Angel Diaz-Lagares 4 , Margherita Iaboni 1 , Danilo Fiore 1 , Valentina Russo 1 , Matilde Todaro 5 , Giulia Romano 6 , Renato Thomas 7 , Giuseppina Cortino 7 , Miriam Gaggianesi 5 , Manel Esteller 4 , Carlo M. Croce 6 , Gerolama Condorelli 1, 2 1 Department of Molecular Medicine and Medical Biotechnology, “Federico II” University of Naples, Naples, Italy 2 IEOS-CNR, Naples, Italy 3 IRCCS-SDN, Naples, Italy 4 Epigenetic and Cancer Biology Program (PEBC) IDIBELL, Hospital Duran I Reynals, Barcelona, Spain 5 Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Lab…
Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment
Genomic imprinting is a form of epigenetic regulation that results in the expression of either the maternally or paternally inherited allele of a subset of genes (Ramowitz and Bartolomei 2011). This imprinted expression of transcripts is crucial for normal mammalian development. In humans, loss-of-imprinting of specific loci results in a number of diseases exemplified by the reciprocal growth phenotypes of the Beckwith-Wiedemann and Silver-Russell syndromes, and the behavioral disorders Angelman and Prader-Willi syndromes (Kagami et al. 2008; Buiting 2010; Choufani et al. 2010; Eggermann 2010; Kelsey 2010; Mackay and Temple 2010). In addition, aberrant imprinting also contributes to multige…
Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR
Metastasis is respoMetastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining imm…
Additional file 8: of A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients
Sequence of primers used by pyrosequencing in the validation assay of candidate genes obtained from 450k array (PPT 143 kb)
Variable maternal methylation overlapping the nc886/vtRNA2-1 locus is locked between hypermethylated repeats and is frequently altered in cancer.
Cancer is as much an epigenetic disease as a genetic one; however, the interplay between these two processes is unclear. Recently, it has been shown that a large proportion of DNA methylation variability can be explained by allele-specific methylation (ASM), either at classical imprinted loci or those regulated by underlying genetic variants. During a recent screen for imprinted differentially methylated regions, we identified the genomic interval overlapping the non-coding nc886 RNA (previously known as vtRNA2-1) as an atypical ASM that shows variable levels of methylation, predominantly on the maternal allele in many tissues. Here we show that the nc886 interval is the first example of a …
Additional file 7: of A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients
Clinical inclusion and exclusion criteria followed to select TNBC patients for the methylation study (PPT 89 kb)