The long non-coding RNA Meg3 mediates imprinted gene expression during stem cell differentiation.

The imprinted Dlk1-Dio3 domain comprises the developmental genes Dlk1 and Rtl1, which are silenced on the maternal chromosome in different cell types. On this parental chromosome, the domain's imprinting control region activates a polycistron that produces the lncRNA Meg3 and many miRNAs (Mirg) and C/D-box snoRNAs (Rian). Although Meg3 lncRNA is nuclear and associates with the maternal chromosome, it is unknown whether it controls gene repression in cis.

Blood co-expression modules identify potential modifier genes of diabetes and lung function in cystic fibrosis.

Cystic fibrosis (CF) is a rare genetic disease that affects the respiratory and digestive systems. Lung disease is variable among CF patients and associated with the development of comorbidities and chronic infections. The rate of lung function deterioration depends not only on the type of mutations in CFTR, the disease-causing gene, but also on modifier genes.

DNA methylation changes in cystic fibrosis: Cause or consequence?

Twin and sibling studies have shown that lung disease severity is variable among cystic fibrosis (CF) patients and affected to the same extent by genetic and nonheritable factors. Genetic factors have been thoroughly assessed, whereas the molecular mechanisms whereby nonheritable factors contribute to the phenotypic variability of CF patients are still unknown. Epigenetic modifications may represent the missing link between nonheritable factors and phenotypic variation in CF.

The HDAC inhibitor SAHA does not rescue CFTR membrane expression in Cystic Fibrosis.

The development of suitable Cystic Fibrosis (CF) models for preclinical bench tests of therapeutic candidates is challenging. Indeed, the validation of molecules to rescue the p.Phe508del-CFTR channel (encoded by the Cystic Fibrosis Transmembrane conductance Regulator gene carrying the p.

DNA methylation at modifier genes of lung disease severity is altered in cystic fibrosis.

Background: Lung disease progression is variable among cystic fibrosis (CF) patients and depends on DNA mutations in the gene, polymorphic variations in disease modifier genes, and environmental exposure. The contribution of genetic factors has been extensively investigated, whereas the mechanism whereby environmental factors modulate the lung disease is unknown. In this project, we hypothesized that (i) reiterative stress alters the epigenome in CF-affected tissues and (ii) DNA methylation variations at disease modifier genes modulate the lung function in CF patients.

Nasal epithelial cells: a tool to study DNA methylation in airway diseases.

A number of chronic airway diseases are characterized by high inflammation and unbalanced activation of the immune response, which lead to tissue damage and progressive reduction of the pulmonary function. Because they are exposed to various environmental stimuli, lung cells are prone to epigenomic changes. Many genes responsible for the immune response and inflammation are tightly regulated by DNA methylation, which suggests that alteration of the epigenome in lung cells may have a considerable impact on the penetrance and/or the severity of airway diseases.

A balance between activating and repressive histone modifications regulates cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo.

The genetic mechanisms that regulate CFTR, the gene responsible for cystic fibrosis, have been widely investigated in cultured cells. However, mechanisms responsible for tissue-specific and time-specific expression are not completely elucidated in vivo. Through the survey of public databases, we found that the promoter of CFTR was associated with bivalent chromatin in human embryonic stem (ES) cells.

DNA replication is altered in Immunodeficiency Centromeric instability Facial anomalies (ICF) cells carrying DNMT3B mutations.

ICF syndrome is a rare autosomal recessive disorder that is characterized by Immunodeficiency, Centromeric instability, and Facial anomalies. In all, 60% of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In ICF cells, constitutive heterochromatin is hypomethylated and decondensed, metaphase chromosomes undergo rearrangements (mainly involving juxtacentromeric regions), and more than 700 genes are aberrantly expressed.

Heterochromatic genes undergo epigenetic changes and escape silencing in immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome.

Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) syndrome is a rare autosomal recessive disorder that is characterized by a marked immunodeficiency, severe hypomethylation of the classical satellites 2 and 3 associated with disruption of constitutive heterochromatin, and facial anomalies. Sixty percent of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In the present study, we have shown that, in ICF lymphoblasts and peripheral blood, juxtacentromeric heterochromatic genes undergo dramatic changes in DNA methylation, indicating that they are bona fide targets of the DNMT3B protein.

Clinical and molecular overview of inherited disorders resulting from epigenomic dysregulation.

Epigenetics is the study of heritable changes in gene expression that occur without a change in the DNA sequence. Most constitutional defects in genes encoding components of the machinery that regulates the epigenome lead to embryonic death. Hypomorphic mutations may be compatible with life, but lead to severe developmental disorders.

BAGE Hypomethylation Is an Early Event in Colon Transformation and Is Frequent in Histologically Advanced Adenomas.

We showed earlier that BAGE (B melanoma antigen) loci are hypermethylated in normal tissues and hypomethylated in 98% of human cancers. More recently, we provided evidence that hypomethylation of BAGE loci represents an informative marker for colon cancer detection. In this study, we show that hypomethylation of BAGE loci was an early event that occurred in 43% of colorectal adenomas.

BAGE hypomethylation, a new epigenetic biomarker for colon cancer detection.

Early detection of colorectal cancer is a decisive step in the successful and complete cure of the disease. Epigenetic markers, in particular, those based on aberrant DNA methylation, can be used to diagnose cancer. B melanoma antigens (BAGE) are a family of genes and truncated genes located in the heterochromatic regions of several human chromosomes.

Mapping of the juxtacentromeric heterochromatin-euchromatin frontier of human chromosome 21.

Euchromatin and heterochromatin are functional compartments of the genome. However, little is known about the structure and the precise location of the heterochromatin-euchromatin boundaries in higher eukaryotes. Constitutive heterochromatin in centromeric regions is associated with (1) specific histone methylation patterns, (2) high levels of DNA methylation, (3) low recombination frequency, and (4) the repression of transcription.

Characterization and expression analysis during embryo development of the mouse ortholog of MLL3.

We characterized the mouse ortholog of the human MLL3 gene and a 10.6 kb-Mll3 transcript. The mouse Mll3 gene comprises 60 exons that encompass 226 kb in chromosome 5.

Frequent DNA hypomethylation of human juxtacentromeric BAGE loci in cancer.

The BAGE (B melanoma antigens) sequence family contains 15 nearly identical sequences that are in the juxtacentromeric regions of chromosomes 9, 13, 18, and 21. BAGE loci are expressed in male germ tissue and in a high percentage of cancers and cancer cell lines. We analyzed the DNA methylation state of the sequences in or near the promoters of the BAGE loci by a quantitative bisulfite and PCR-based assay (multiplex COBRA) using MboI and HphI in 18 somatic tissue samples, 4 testis and 4 sperm samples, and 48 tumors and tumor cell lines.

Juxtacentromeric region of human chromosome 21: a boundary between centromeric heterochromatin and euchromatic chromosome arms.

We have analysed the genomic structure and transcriptional activity of a 2.3-Mb genomic sequence in the juxtacentromeric region of human chromosome 21. Our work shows that this region comprises two different chromosome domains.

BAGE genes generated by juxtacentromeric reshuffling in the Hominidae lineage are under selective pressure.

In this paper, we show that the BAGE (B melanoma antigen) gene family was generated by chromosome rearrangements that occurred during the evolution of hominoids. An 84-kb DNA fragment derived from the phylogenetic 7q36 region was duplicated in the juxtacentromeric region of either chromosome 13 or chromosome 21. The duplicated region contained a fragment of the MLL3 gene, which, after juxtacentromeric reshuffling, generated the ancestral BAGE gene.

New BAGE (B melanoma antigen) genes mapping to the juxtacentromeric regions of human chromosomes 13 and 21 have a cancer/testis expression profile.

A first BAGE (B melanoma antigen) gene, BAGE1, was identified because it encodes a human tumour antigen recognised by a cytolytic T lymphocyte. Here, we characterised five new BAGE genes mapping to the juxtacentromeric regions of human chromosomes 13 and 21 and nine BAGE gene fragments mapping to the juxtacentromeric regions of chromosomes 9, 13, 18, and 21. Genes and gene fragments share extensive regions of 90-99% nucleotide identity.

MLL3, a new human member of the TRX/MLL gene family, maps to 7q36, a chromosome region frequently deleted in myeloid leukaemia.

We characterized MLL3, a new human member of the TRX/MLL gene family. MLL3 is expressed in peripheral blood, placenta, pancreas, testes, and foetal thymus and is weakly expressed in heart, brain, lung, liver, and kidney. It encodes a predicted protein of 4911 amino acids containing two plant homeo domains (PHD), an ATPase alpha_beta signature, a high mobility group, a SET (Suppressor of variegation, Enhancer of zeste, Trithorax) and two FY (phenylalanine tyrosine)-rich domains.