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Oct4-Mediated Inhibition of Lsd1 Activity Promotes the Active and Primed State of Pluripotency Enhancers.

Authors:
Lama AlAbdi Debapriya Saha Ming He Mohd Saleem Dar Sagar M Utturkar Putu Ayu Sudyanti Stephen McCune Brice H Spears James A Breedlove Nadia A Lanman Humaira Gowher

Cell Rep 2020 02;30(5):1478-1490.e6

Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA; Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. Electronic address:

An aberrant increase in pluripotency gene (PpG) expression due to enhancer reactivation could induce stemness and enhance the tumorigenicity of cancer stem cells. Silencing of PpG enhancers (PpGe) during embryonic stem cell differentiation involves Lsd1-mediated H3K4me1 demethylation and DNA methylation. Here, we observed retention of H3K4me1 and DNA hypomethylation at PpGe associated with a partial repression of PpGs in F9 embryonal carcinoma cells (ECCs) post-differentiation. H3K4me1 demethylation in F9 ECCs could not be rescued by Lsd1 overexpression. Given our observation that H3K4me1 demethylation is accompanied by strong Oct4 repression in P19 ECCs, we tested if Oct4 interaction with Lsd1 affects its catalytic activity. Our data show a dose-dependent inhibition of Lsd1 activity by Oct4 and retention of H3K4me1 at PpGe in Oct4-overexpressing P19 ECCs. These data suggest that Lsd1-Oct4 interaction in cancer stem cells could establish a "primed" enhancer state that is susceptible to reactivation, leading to aberrant PpG expression.

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http://dx.doi.org/10.1016/j.celrep.2019.11.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316367PMC
February 2020

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Simplified MethylRAD Sequencing to Detect Changes in DNA Methylation at Enhancer Elements in Differentiating Embryonic Stem Cells.

Authors:
Debapriya Saha Allison B Norvil Nadia A Lanman Humaira Gowher

Epigenomes 2020 Dec 1;4(4). Epub 2020 Oct 1.

Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA.

Differential DNA methylation is characteristic of gene regulatory regions, such as enhancers, which mostly constitute low or intermediate CpG content in their DNA sequence. Consequently, quantification of changes in DNA methylation at these sites is challenging. Given that DNA methylation across most of the mammalian genome is maintained, the use of genome-wide bisulfite sequencing to measure fractional changes in DNA methylation at specific sites is an overexertion which is both expensive and cumbersome. Read More

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Authors:
Brian C-H Chiu Chang Chen Qiancheng You Rudyard Chiu Girish Venkataraman Chang Zeng Zhou Zhang Xiaolong Cui Sonali M Smith Chuan He Wei Zhang

NPJ Genom Med 2021 Feb 11;6(1):11. Epub 2021 Feb 11.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

The 5-methylcytosines (5mC) have been implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the role of 5-hydroxymethylcytosines (5hmC) that are generated from 5mC through active demethylation, in lymphomagenesis is unknown. We profiled genome-wide 5hmC in circulating cell-free DNA (cfDNA) from 73 newly diagnosed patients with DLBCL and FL. Read More

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LSD1: more than demethylation of histone lysine residues.

Authors:
Bruno Perillo Alfonso Tramontano Antonio Pezone Antimo Migliaccio

Exp Mol Med 2020 12 14;52(12):1936-1947. Epub 2020 Dec 14.

Dipartimento di Medicina di Precisione Università della Campania "L. Vanvitelli", 80138, Naples, Italy.

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. Read More

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STAT5 Regulation of Sex-Dependent Hepatic CpG Methylation at Distal Regulatory Elements Mapping to Sex-Biased Genes.

Authors:
Pengying Hao David J Waxman

Mol Cell Biol 2021 01 25;41(2). Epub 2021 Jan 25.

Department of Biology and Bioinformatics Program, Boston University, Boston, Massachusetts, USA

Growth hormone-activated STAT5b is an essential regulator of sex-differential gene expression in mouse liver; however, its impact on hepatic gene expression and epigenetic responses is poorly understood. Here, we found a substantial, albeit incomplete loss of liver sex bias in hepatocyte-specific STAT5a/STAT5b (collectively, STAT5)-deficient mouse liver. In male liver, many male-biased genes were downregulated in direct association with the loss of STAT5 binding; many female-biased genes, which show low STAT5 binding, were derepressed, indicating an indirect mechanism for repression by STAT5. Read More

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Immediate and durable effects of maternal tobacco consumption alter placental DNA methylation in enhancer and imprinted gene-containing regions.

Authors:
Sophie Rousseaux Emie Seyve Florent Chuffart Ekaterina Bourova-Flin Meriem Benmerad Marie-Aline Charles Anne Forhan Barbara Heude Valérie Siroux Remy Slama Jorg Tost Daniel Vaiman Saadi Khochbin Johanna Lepeule

BMC Med 2020 10 7;18(1):306. Epub 2020 Oct 7.

Université Grenoble Alpes, Inserm, CNRS, IAB, 38000, Grenoble, France.

Background: Although exposure to cigarette smoking during pregnancy has been associated with alterations of DNA methylation in the cord blood or placental cells, whether such exposure before pregnancy could induce epigenetic alterations in the placenta of former smokers has never been investigated.

Methods: Our approach combined the analysis of placenta epigenomic (ENCODE) data with newly generated DNA methylation data obtained from 568 pregnant women, the largest cohort to date, either actively smoking during their pregnancy or formerly exposed to tobacco smoking.

Results: This strategy resulted in several major findings. Read More

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October 2020
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