Search results for "Epigenetics"

Polycomb-like 2 Associates with PRC2 and Regulates Transcriptional Networks during Mouse Embryonic Stem Cell Self-Renewal and Differentiation

2010

SummaryPolycomb group (PcG) proteins are conserved epigenetic transcriptional repressors that control numerous developmental gene expression programs and have recently been implicated in modulating embryonic stem cell (ESC) fate. We identified the PcG protein PCL2 (polycomb-like 2) in a genome-wide screen for regulators of self-renewal and pluripotency and predicted that it would play an important role in mouse ESC-fate determination. Using multiple biochemical strategies, we provide evidence that PCL2 is a Polycomb Repressive Complex 2 (PRC2)-associated protein in mouse ESCs. Knockdown of Pcl2 in ESCs resulted in heightened self-renewal characteristics, defects in differentiation, and alte…

Colorectal Cancer Stem Cells: From the Crypt to the Clinic

2014

Since their first discovery, investigations of colorectal cancer stem cells (CSCs) have revealed some unexpected properties, including a high degree of heterogeneity and plasticity. By exploiting a combination of genetic, epigenetic, and microenvironmental factors, colorectal CSCs metastasize, resist chemotherapy, and continually adapt to a changing microenvironment, representing a formidable challenge to cancer eradication. Here, we review the current understanding of colorectal CSCs, including their origin, relationship to stem cells of the intestine, phenotypic characterization, and underlying regulatory mechanisms. We also discuss limitations to current preclinical models of colorectal …

Poly-ADP-Ribose (PAR) as an epigenetic flag

2009

Epigenetics is the study of hereditable chromatin modifications, such as DNA methylation, histone modifications, and nucleosome-remodelling, which occur without alterations to the DNA sequence. The establishment of different epigenetic states in eukaryotes depends on regulatory mechanisms that induce structural changes in chromatin in response to environmental and cellular cues. Two classes of enzymes modulate chromatin accessibility: chromatin-covalent modifiers and ATP-dependent chromatin remodelling complexes. The first class of enzymes catalyzes covalent modifications of DNA as well as the amino- and carboxy-terminal tails of histones, while the second uses the energy of ATP hydrolysis …

Germline correction of an epimutation related to Silver-Russell syndrome.

2015

Like genetic mutations, DNA methylation anomalies or epimutations can disrupt gene expression and lead to human diseases. However, unlike genetic mutations, epimutations can in theory be reverted through developmental epigenetic reprograming, which should limit their transmission across generations. Following the request for a parental project of a patient diagnosed with Silver-Russell syndrome (SRS), and the availability of both somatic and spermatozoa DNA from the proband and his father, we had the exceptional opportunity to evaluate the question of inheritance of an epimutation. We provide here for the first time evidence for efficient reversion of a constitutive epimutation in the sperm…

MYC and EGR1 synergize to trigger tumor cell death by controlling NOXA and BIM transcription upon treatment with the proteasome inhibitor bortezomib

2014

The c-MYC (MYC afterward) oncogene is well known for driving numerous oncogenic programs. However, MYC can also induce apoptosis and this function of MYC warrants further clarification. We report here that a clinically relevant proteasome inhibitor significantly increases MYC protein levels and that endogenous MYC is necessary for the induction of apoptosis. This kind of MYC-induced cell death is mediated by enhanced expression of the pro-apoptotic BCL2 family members NOXA and BIM. Quantitative promoter-scanning chromatin immunoprecipitations (qChIP) further revealed binding of MYC to the promoters of NOXA and BIM upon proteasome inhibition, correlating with increased transcription. Both pr…

A TR-FRET based functional assay for screening activators of CARM1

2013

Epigenome is an emerging field that demands selective cell-permeable chemical probes to perturb, especially in vivo, the activity of specific enzymes involved in modulating the epigenetic codes. Coactivator Associated Arginine (R) Methyltransferase 1 (CARM1) is a coactivator of estrogen receptor α (ERα), the main target in human breast cancer. We previously showed that overexpression of CARM1 by two-fold in MCF7 breast cancer cells increased the expression of ERα-target genes involved in differentiation and reduced cell proliferation, leading to the hypothesis that activating CARM1 by chemical activators may be therapeutically effective in breast cancer. Selective, potent, cell-permeable CA…

"Omics" of HER2-positive breast cancer.

2013

HER2/neu amplification/overexpression is the only somatic mutation widely considered to be a marker of disease outcome and response to treatment in breast cancer. Pathologists have made large efforts to achieve accuracy in characterizing HER2/neu status. The introduction of transtuzumab contributed to development of additional measures to identify sensitive and resistant subclasses of HER2/neu-positive tumors. In this article, we describe the latest advances in HER2/neu status diagnostic assessment and the most relevant research emerging from ‘‘Omics’’ (genomics, epigenetics, transcriptomics, and proteomics) studies on HER2/neu-positive breast cancer. A large quantity of biomarkers from dif…

CiliaCarta: An integrated and validated compendium of ciliary genes

2019

The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse…

Autism spectrum disorders: possible implications of BDNF modulation through epigenetics

2013

Phytochemical Indicaxanthin Inhibits Colon Cancer Cell Growth and Affects the DNA Methylation Status by Influencing Epigenetically Modifying Enzyme E…

2015

<b><i>Background:</i></b> Recently, we have shown anti-proliferative and pro-apoptotic effects of indicaxanthin associated with epigenetic modulation of the onco-suppressor <i>p16</i><sup><i>INK4a</i></sup> in the human colon cancer cell line CACO2. In the present study, the epigenetic activity of indicaxanthin and the mechanisms involved were further investigated in other colorectal cancer cell lines. <b><i>Methods:</i></b> LOVO1, CACO2, HT29, HCT116, and DLD1 cells were used to evaluate the potential influence of consistent dietary concentrations of indicaxanthin on DNA methylation, and the epigenetic mech…