Fine-tuning of gene expression through the Mettl3-Mettl14-Dnmt1 axis controls ESC differentiation.

The marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links N6-methyladenosine (mA), installed on RNA by the METTL3-METTL14 methyltransferase complex, to histone modifications, but the link between mA and DNA methylation remains scarcely explored. This study shows that METTL3-METTL14 recruits the DNA methyltransferase DNMT1 to chromatin for gene-body methylation.

Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila.

Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases and catalyze the transition of 5mC to 5hmC in DNA.

SRSF2 plays an unexpected role as reader of mC on mRNA, linking epitranscriptomics to cancer.

A common mRNA modification is 5-methylcytosine (mC), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of mC and impaired SRSF2 mC binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in mC recognition and the impact of the prevalent leukemia-associated mutation SRSF2.

Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates the axon guidance genes and in .

Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases enzymes catalyzing the transition of 5mC to 5hmC in DNA and have recently been shown to have the same function in messenger RNAs in both vertebrates and in Drosophila.

Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila.

Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases and catalyze the transition of 5mC to 5hmC in DNA.

Improving Infinium MethylationEPIC data processing: re-annotation of enhancers and long noncoding RNA genes and benchmarking of normalization methods.

Illumina Infinium DNA Methylation (5mC) arrays are a popular technology for low-cost, high-throughput, genome-scale measurement of 5mC distribution, especially in cancer and other complex diseases. After the success of its HumanMethylation450 array (450k), Illumina released the MethylationEPIC array (850k) featuring increased coverage of enhancers. Despite the widespread use of 850k, analysis of the corresponding data remains suboptimal: it still relies mostly on Illumina's default annotation, which underestimates enhancerss and long noncoding RNAs.

Novel role of UHRF1 in the epigenetic repression of the latent HIV-1.

Background: The multiplicity, heterogeneity, and dynamic nature of human immunodeficiency virus type-1 (HIV-1) latency mechanisms are reflected in the current lack of functional cure for HIV-1. Accordingly, all classes of latency-reversing agents (LRAs) have been reported to present variable ex vivo potencies. Here, we investigated the molecular mechanisms underlying the potency variability of one LRA: the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-AzadC).

Analyses of DNA Methylation Profiling in the Diagnosis of Intramedullary Astrocytomas.

Intramedullary astrocytomas (IMAs) consist of a heterogeneous group of rare central nervous system (CNS) tumors associated with variable outcomes. A DNA methylation-based classification approach has recently emerged as a powerful tool to further classify CNS tumors. However, no DNA methylation-related studies specifically addressing to IMAs have been performed yet.

The chromatin remodelling protein LSH/HELLS regulates the amount and distribution of DNA hydroxymethylation in the genome.

Ten-Eleven Translocation (TET) proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) leading to a dynamic epigenetic state of DNA that can influence transcription and chromatin organization. While TET proteins interact with complexes involved in transcriptional repression and activation, the overall understanding of the molecular mechanisms involved in TET-mediated regulation of gene expression still remains limited. Here, we show that TET proteins interact with the chromatin remodelling protein lymphoid-specific helicase (LSH/HELLS) and .

Functional role of Tet-mediated RNA hydroxymethylcytosine in mouse ES cells and during differentiation.

Tet-enzyme-mediated 5-hydroxymethylation of cytosines in DNA plays a crucial role in mouse embryonic stem cells (ESCs). In RNA also, 5-hydroxymethylcytosine (5hmC) has recently been evidenced, but its physiological roles are still largely unknown. Here we show the contribution and function of this mark in mouse ESCs and differentiating embryoid bodies.

Circulating unmethylated CHTOP and INS DNA fragments provide evidence of possible islet cell death in youth with obesity and diabetes.

Background: Identification of islet β cell death prior to the onset of type 1 diabetes (T1D) or type 2 diabetes (T2D) might allow for interventions to protect β cells and reduce diabetes risk. Circulating unmethylated DNA fragments arising from the human INS gene have been proposed as biomarkers of β cell death, but this gene alone may not be sufficiently specific to report β cell death.

Results: To identify new candidate genes whose CpG sites may show greater specificity for β cells, we performed unbiased DNA methylation analysis using the Infinium HumanMethylation 450 array on 64 human islet preparations and 27 non-islet human tissues.

TET2-Dependent Hydroxymethylome Plasticity Reduces Melanoma Initiation and Progression.

Although numerous epigenetic aberrancies accumulate in melanoma, their contribution to initiation and progression remain unclear. The epigenetic mark 5-hydroxymethylcytosine (5hmC), generated through TET-mediated DNA modification, is now referred to as the sixth base of DNA and has recently been reported as a potential biomarker for multiple types of cancer. Loss of 5hmC is an epigenetic hallmark of melanoma, but whether a decrease in 5hmc levels contributes directly to pathogenesis or whether it merely results from disease progression-associated epigenetic remodeling remains to be established.

Comprehensive identification of long noncoding RNAs in colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers in humans and a leading cause of cancer-related deaths worldwide. As in the case of other cancers, CRC heterogeneity leads to a wide range of clinical outcomes and complicates therapy. Over the years, multiple factors have emerged as markers of CRC heterogeneity, improving tumor classification and selection of therapeutic strategies.

Immunity drives regulation in cancer through NF-κB.

Ten-eleven translocation enzymes (TET1, TET2, and TET3), which induce DNA demethylation and gene regulation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), are often down-regulated in cancer. We uncover, in basal-like breast cancer (BLBC), genome-wide 5hmC changes related to regulation. We further demonstrate that repression is associated with high expression of immune markers and high infiltration by immune cells.

The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes.

Cytotoxic CD4 (CD4) T cells are emerging as an important component of antiviral and antitumor immunity, but the molecular basis of their development remains poorly understood. In the context of human cytomegalovirus infection, a significant proportion of CD4 T cells displays cytotoxic functions. We observed that the transcriptional program of these cells was enriched in CD8 T cell lineage genes despite the absence of ThPOK downregulation.

DNA methylation-based immune response signature improves patient diagnosis in multiple cancers.

Background: The tumor immune response is increasingly associated with better clinical outcomes in breast and other cancers. However, the evaluation of tumor-infiltrating lymphocytes (TILs) relies on histopathological measurements with limited accuracy and reproducibility. Here, we profiled DNA methylation markers to identify a methylation of TIL (MeTIL) signature that recapitulates TIL evaluations and their prognostic value for long-term outcomes in breast cancer (BC).

FOXP1 is a regulator of quiescence in healthy human CD4 T cells and is constitutively repressed in T cells from patients with lymphoproliferative disorders.

The forkhead box P1 (FOXP1) transcription factor has been shown to regulate the generation and maintenance of quiescent naïve murine T cells. In humans, FOXP1 expression has been correlated with overall survival in patients with peripheral T-cell lymphoma (PTCL), although its regulatory role in T-cell function is currently unknown. We found that FOXP1 is normally expressed in all human leukocyte subpopulations.

Portraying breast cancers with long noncoding RNAs.

Evidence is emerging that long noncoding RNAs (lncRNAs) may play a role in cancer development, but this role is not yet clear. We performed a genome-wide transcriptional survey to explore the lncRNA landscape across 995 breast tissue samples. We identified 215 lncRNAs whose genes are aberrantly expressed in breast tumors, as compared to normal samples.

The interplay between the lysine demethylase KDM1A and DNA methyltransferases in cancer cells is cell cycle dependent.

DNA methylation and histone modifications are key epigenetic regulators of gene expression, and tight connections are known between the two. DNA methyltransferases are upregulated in several tumors and aberrant DNA methylation profiles are a cancer hallmark. On the other hand, histone demethylases are upregulated in cancer cells.

A comprehensive overview of Infinium HumanMethylation450 data processing.

Infinium HumanMethylation450 beadarray is a popular technology to explore DNA methylomes in health and disease, and there is a current explosion in the use of this technique. Despite experience acquired from gene expression microarrays, analyzing Infinium Methylation arrays appeared more complex than initially thought and several difficulties have been encountered, as those arrays display specific features that need to be taken into consideration during data processing. Here, we review several issues that have been highlighted by the scientific community, and we present an overview of the general data processing scheme and an evaluation of the different normalization methods available to date to guide the 450K users in their analysis and data interpretation.