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Cells Nov 2021Nutritional intake impacts the human epigenome by directing epigenetic pathways in normal cell development via as yet unknown molecular mechanisms. Consequently,...
Nutritional intake impacts the human epigenome by directing epigenetic pathways in normal cell development via as yet unknown molecular mechanisms. Consequently, imbalance in the nutritional intake is able to dysregulate the epigenetic profile and drive cells towards malignant transformation. Here we present a novel epigenetic effect of the essential nutrient, NAD. We demonstrate that impairment of DNMT1 enzymatic activity by NAD-promoted ADP-ribosylation leads to demethylation and transcriptional activation of the gene, suggesting the existence of an unknown NAD-controlled region within the locus. In addition to the molecular events, NAD- treated cells exhibit significant morphological and phenotypical changes that correspond to myeloid differentiation. Collectively, these results delineate a novel role for NAD in cell differentiation, and indicate novel nutri-epigenetic strategies to regulate and control gene expression in human cells.
Topics: CCAAT-Enhancer-Binding Proteins; Cell Differentiation; Cell Line; DNA Demethylation; DNA Methylation; Humans; Mitochondria; Myeloid Cells; NAD; Neoplasms; Oxidative Phosphorylation; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Promoter Regions, Genetic; RNA, Messenger; Transcription, Genetic
PubMed: 34831209
DOI: 10.3390/cells10112986 -
Experimental and Therapeutic Medicine Jul 2021Histone lysine demethylation modification is a critical epigenetic modification. Lysine demethylase 2A (KDM2A), a Jumonji C domain-containing demethylase, demethylates... (Review)
Review
Histone lysine demethylation modification is a critical epigenetic modification. Lysine demethylase 2A (KDM2A), a Jumonji C domain-containing demethylase, demethylates the dimethylated H3 lysine 36 (H3K36) residue and exerts little or no activity on monomethylated and trimethylated H3K36 residues. KDM2A expression is regulated by several factors, such as microRNAs, and the phosphorylation of KDM2A also plays a vital role in its function. KDM2A mainly recognizes the unmethylated region of CpG islands and subsequently demethylates histone H3K36 residues. In addition, KDM2A recognizes and binds to phosphorylated proteins, and promotes their ubiquitination and degradation. KDM2A plays an important role in chromosome remodeling and gene transcription, and is involved in cell proliferation and differentiation, cell metabolism, heterochromosomal homeostasis and gene stability. Notably, KDM2A is crucial for tumorigenesis and progression. In the present review, the documented biological functions of KDM2A in physiological and pathological processes are comprehensively summarized.
PubMed: 34007332
DOI: 10.3892/etm.2021.10155 -
Clinical Epigenetics Aug 2023Promoter hypermethylation of tumour suppressor genes is frequently observed during the malignant transformation of colorectal cancer (CRC). However, whether this...
BACKGROUND
Promoter hypermethylation of tumour suppressor genes is frequently observed during the malignant transformation of colorectal cancer (CRC). However, whether this epigenetic mechanism is functional in cancer or is a mere consequence of the carcinogenic process remains to be elucidated.
RESULTS
In this work, we performed an integrative multi-omic approach to identify gene candidates with strong correlations between DNA methylation and gene expression in human CRC samples and a set of 8 colon cancer cell lines. As a proof of concept, we combined recent CRISPR-Cas9 epigenome editing tools (dCas9-TET1, dCas9-TET-IM) with a customized arrayed gRNA library to modulate the DNA methylation status of 56 promoters previously linked with strong epigenetic repression in CRC, and we monitored the potential functional consequences of this DNA methylation loss by means of a high-content cell proliferation screen. Overall, the epigenetic modulation of most of these DNA methylated regions had a mild impact on the reactivation of gene expression and on the viability of cancer cells. Interestingly, we found that epigenetic reactivation of RSPO2 in the tumour context was associated with a significant impairment in cell proliferation in p53 cancer cell lines, and further validation with human samples demonstrated that the epigenetic silencing of RSPO2 is a mid-late event in the adenoma to carcinoma sequence.
CONCLUSIONS
These results highlight the potential role of DNA methylation as a driver mechanism of CRC and paves the way for the identification of novel therapeutic windows based on the epigenetic reactivation of certain tumour suppressor genes.
Topics: Humans; DNA Methylation; DNA Demethylation; Epigenesis, Genetic; Carcinogenesis; Colonic Neoplasms; Mixed Function Oxygenases; Proto-Oncogene Proteins
PubMed: 37612734
DOI: 10.1186/s13148-023-01546-1 -
Experimental & Molecular Medicine Dec 2020Lysine-specific histone demethylase 1 (LSD1) represents the first example of an identified nuclear protein with histone demethylase activity. In particular, it plays a... (Review)
Review
Lysine-specific histone demethylase 1 (LSD1) represents the first example of an identified nuclear protein with histone demethylase activity. In particular, it plays a special role in the epigenetic regulation of gene expression, as it removes methyl groups from mono- and dimethylated lysine 4 and/or lysine 9 on histone H3 (H3K4me1/2 and H3K9me1/2), behaving as a repressor or activator of gene expression, respectively. Moreover, it has been recently found to demethylate monomethylated and dimethylated lysine 20 in histone H4 and to contribute to the balance of several other methylated lysine residues in histone H3 (i.e., H3K27, H3K36, and H3K79). Furthermore, in recent years, a plethora of nonhistone proteins have been detected as targets of LSD1 activity, suggesting that this demethylase is a fundamental player in the regulation of multiple pathways triggered in several cellular processes, including cancer progression. In this review, we analyze the molecular mechanism by which LSD1 displays its dual effect on gene expression (related to the specific lysine target), placing final emphasis on the use of pharmacological inhibitors of its activity in future clinical studies to fight cancer.
Topics: Alternative Splicing; Animals; Biomarkers, Tumor; Demethylation; Epigenesis, Genetic; Gene Expression Regulation; Histone Demethylases; Histones; Humans; Lysine; Molecular Targeted Therapy; Protein Binding; Protein Processing, Post-Translational; Protein Stability; Receptors, Cytoplasmic and Nuclear; Structure-Activity Relationship
PubMed: 33318631
DOI: 10.1038/s12276-020-00542-2 -
Mutation Research. Reviews in Mutation... 2021APE2 is a rising vital player in the maintenance of genome and epigenome integrity. In the past several years, a series of studies have shown the critical roles and... (Review)
Review
APE2 is a rising vital player in the maintenance of genome and epigenome integrity. In the past several years, a series of studies have shown the critical roles and functions of APE2. We seek to provide the first comprehensive review on several aspects of APE2 in genome and epigenome integrity. We first summarize the distinct functional domains or motifs within APE2 including EEP (endonuclease/exonuclease/phosphatase) domain, PIP box and Zf-GRF motifs from eight species (i.e., Homo sapiens, Mus musculus, Xenopus laevis, Ciona intestinalis, Arabidopsis thaliana, Schizosaccharomyces pombe, Saccharomyces cerevisiae, and Trypanosoma cruzi). Then we analyze various APE2 nuclease activities and associated DNA substrates, including AP endonuclease, 3'-phosphodiesterase, 3'-phosphatase, and 3'-5' exonuclease activities. We also examine several APE2 interaction proteins, including PCNA, Chk1, APE1, Myh1, and homologous recombination (HR) factors such as Rad51, Rad52, BRCA1, BRCA2, and BARD1. Furthermore, we provide insights into the roles of APE2 in various DNA repair pathways (base excision repair, single-strand break repair, and double-strand break repair), DNA damage response (DDR) pathways (ATR-Chk1 and p53-dependent), immunoglobulin class switch recombination and somatic hypermutation, as well as active DNA demethylation. Lastly, we summarize critical functions of APE2 in growth, development, and diseases. In this review, we provide the first comprehensive perspective which dissects all aspects of the multiple-function protein APE2 in genome and epigenome integrity.
Topics: Animals; Arabidopsis Proteins; DNA Damage; DNA Demethylation; DNA Repair; Endonucleases; Epigenome; Humans; Immunity; Rad51 Recombinase; Saccharomyces cerevisiae
PubMed: 34083046
DOI: 10.1016/j.mrrev.2020.108347 -
Nature Communications May 2023Eukaryotes produce highly modified sterols, including cholesterol, essential to eukaryotic physiology. Although few bacterial species are known to produce sterols, de...
Eukaryotes produce highly modified sterols, including cholesterol, essential to eukaryotic physiology. Although few bacterial species are known to produce sterols, de novo production of cholesterol or other complex sterols in bacteria has not been reported. Here, we show that the marine myxobacterium Enhygromyxa salina produces cholesterol and provide evidence for further downstream modifications. Through bioinformatic analysis we identify a putative cholesterol biosynthesis pathway in E. salina largely homologous to the eukaryotic pathway. However, experimental evidence indicates that complete demethylation at C-4 occurs through unique bacterial proteins, distinguishing bacterial and eukaryotic cholesterol biosynthesis. Additionally, proteins from the cyanobacterium Calothrix sp. NIES-4105 are also capable of fully demethylating sterols at the C-4 position, suggesting complex sterol biosynthesis may be found in other bacterial phyla. Our results reveal an unappreciated complexity in bacterial sterol production that rivals eukaryotes and highlight the complicated evolutionary relationship between sterol biosynthesis in the bacterial and eukaryotic domains.
Topics: Sterols; Bacteria; Cholesterol; Phytosterols; Eukaryota
PubMed: 37217541
DOI: 10.1038/s41467-023-38638-8 -
Cells Nov 2021Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSC) provide a powerful model system to uncover fundamental mechanisms that control cellular identity... (Review)
Review
Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSC) provide a powerful model system to uncover fundamental mechanisms that control cellular identity during mammalian development. Histone methylation governs gene expression programs that play a key role in the regulation of the balance between self-renewal and differentiation of ESCs. Lysine-specific demethylase 1 (LSD1, also known as KDM1A), the first identified histone lysine demethylase, demethylates H3K4me1/2 and H3K9me1/2 at target loci in a context-dependent manner. Moreover, it has also been shown to demethylate non-histone substrates playing a central role in the regulation of numerous cellular processes. In this review, we summarize current knowledge about LSD1 and the molecular mechanism by which LSD1 influences the stem cells state, including the regulatory circuitry underlying self-renewal and pluripotency.
Topics: Animals; Cell Differentiation; Cell Self Renewal; Cellular Reprogramming; DNA Methylation; Histone Demethylases; Humans; Stem Cells
PubMed: 34831474
DOI: 10.3390/cells10113252 -
Science (New York, N.Y.) Dec 2022Active DNA demethylation maintains enhancer activity in nonproliferating cells but can damage DNA.
Active DNA demethylation maintains enhancer activity in nonproliferating cells but can damage DNA.
Topics: DNA Demethylation; Macrophages; Neurons; Enhancer Elements, Genetic; Humans; DNA Breaks, Single-Stranded
PubMed: 36454845
DOI: 10.1126/science.adf3171 -
Neuroendocrinology 2022Neurons expressing estrogen receptor (ER) ɑ in the arcuate (ARC) and ventromedial (VMH) nuclei of the hypothalamus sex-specifically control energy homeostasis, sexual...
INTRODUCTION
Neurons expressing estrogen receptor (ER) ɑ in the arcuate (ARC) and ventromedial (VMH) nuclei of the hypothalamus sex-specifically control energy homeostasis, sexual behavior, and bone density. Females have more ERɑ neurons in the VMH and ARC than males, and the sex difference in the VMH is eliminated by neonatal treatment with testosterone or a DNA methylation inhibitor.
OBJECTIVE
Here, we tested the roles of testosterone and DNA methylation/demethylation in development of ERɑ in the ARC.
METHODS
ERɑ was examined at birth and weaning in mice that received vehicle or testosterone subcutaneously, and vehicle or DNA methyltransferase inhibitor intracerebroventricularly, as neonates. To examine effects of DNA demethylation on the ERɑ cell number in the ARC, mice were treated neonatally with small interfering RNAs against ten-eleven translocase enzymes. The methylation status of the ERɑ gene (Esr1) was determined in the ARC and VMH using pyrosequencing of bisulfite-converted DNA.
RESULTS
A sex difference in ERɑ in the ARC, favoring females, developed between birth and weaning and was due to programming effects of testosterone. Neonatal inhibition of DNA methylation decreased ERɑ in the ARC of females, and an inhibition of
de methylation increased ERɑ in the ARC of males. The promoter region of Esr1 exhibited a small sex difference in percent of total methylation in the ARC (females > males) that was opposite to that in the VMH (males > females).CONCLUSION
DNA methylation and demethylation regulate ERɑ cell number in the ARC, and methylation correlates with activation of Esr1 in this region.
Topics: Animals; Arcuate Nucleus of Hypothalamus; DNA Methylation; Demethylation; Estrogen Receptor alpha; Female; Male; Mice; Sex Characteristics; Testosterone
PubMed: 34547753
DOI: 10.1159/000519671 -
Science Advances Jun 2020DNA demethylation is important for the erasure of DNA methylation. The role of DNA demethylation in plant development remains poorly understood. Here, we found extensive...
DNA demethylation is important for the erasure of DNA methylation. The role of DNA demethylation in plant development remains poorly understood. Here, we found extensive DNA demethylation in the CHH context around pericentromeric regions and DNA demethylation in the CG, CHG, and CHH contexts at discrete genomic regions during ectopic xylem tracheary element (TE) differentiation. While loss of pericentromeric methylation occurs passively, DNA demethylation at a subset of regions relies on active DNA demethylation initiated by DNA glycosylases ROS1, DML2, and DML3. The and mutations impair ectopic TE differentiation and xylem development in the young roots of seedlings. Active DNA demethylation targets and regulates many genes for TE differentiation. The defect of xylem development in is proposed to be caused by dysregulation of multiple genes. Our study identifies a role of active DNA demethylation in vascular development and reveals an epigenetic mechanism for TE differentiation.
Topics: Arabidopsis; Arabidopsis Proteins; DNA Demethylation; DNA Methylation; Gene Expression Regulation, Plant; Nuclear Proteins; Protein-Tyrosine Kinases; Proto-Oncogene Proteins
PubMed: 32637594
DOI: 10.1126/sciadv.aaz2963