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Andréa Geoffroy, Racha Kerek, Grégory Pourié, Déborah Helle, Jean-Louis Guéant, Jean-Luc Daval, Carine Bossenmeyer-Pourié
The micronutrients folate and vitamin B12 are essential for the proper development of the central nervous system, and their deficiency during pregnancy has been associated with a wide range of disorders. They act as methyl donors in the one-carbon metabolism which critically influences epigenetic mechanisms. In order to depict further underlying mechanisms, we investigated the role of let-7 and miR-34, two microRNAs regulated by methylation, on a rat model of maternal deficiency. In several countries, public health policies recommend periconceptional supplementation with folic acid...
August 17, 2016: Molecular Neurobiology
Lacey S Williams, Hyung-Goo Kim, Vera M Kalscheuer, J Matthew Tuck, Lynn P Chorich, Megan E Sullivan, Allison Falkenstrom, Richard H Reindollar, Lawrence C Layman
BACKGROUND: Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, or the congenital absence of uterus and vagina, is the most severe anomaly of the female reproductive tract. It affects 1 in 5,000 females, and is the second most common cause of primary amenorrhea. The etiology remains unknown in most patients, although four single gene defects and some repetitive copy number variants (CNVs) have been identified. Translocations in MRKH patients are very rare, and reported only in three patients previously without breakpoint mapping...
2016: Molecular Cytogenetics
Vineet Mohanty, Amar Shah, Elise Allender, M Rizwan Siddiqui, Sarah Monick, Shunsuke Ichi, Barbara Mania-Farnell, David G McLone, Tadanori Tomita, Chandra Shekhar Mayanil
Prenatal folic acid (FA) supplementation prevents neural tube defects. Folate receptor alpha (FRα) is critical for embryonic development, including neural crest (NC) development. Previously we showed that FRα translocates to the nucleus in response to FA, where it acts as a transcription factor. In this study we examined if FA through interaction with FRα regulates stem cell characteristics of cranial neural crest cells (CNCCs)-critical for normal development. We hypothesized that FRα up-regulates coding genes and simultaneously down-regulates non-coding miRNA which targets coding genes in CNCCs...
June 14, 2016: Stem Cells
Alexandra Popa, Kevin Lebrigand, Pascal Barbry, Rainer Waldmann
BACKGROUND: Open reading frames are common in long noncoding RNAs (lncRNAs) and 5'UTRs of protein coding transcripts (uORFs). The question of whether those ORFs are translated was recently addressed by several groups using ribosome profiling. Most of those studies concluded that certain lncRNAs and uORFs are translated, essentially based on computational analysis of ribosome footprints. However, major discrepancies remain on the scope of translation and the translational status of individual ORFs...
2016: BMC Genomics
Sibylle Mitschka, Thomas Ulas, Tobias Goller, Karin Schneider, Angela Egert, Jérôme Mertens, Oliver Brüstle, Hubert Schorle, Marc Beyer, Kathrin Klee, Jia Xue, Patrick Günther, Kevin Bassler, Joachim L Schultze, Waldemar Kolanus
Regulatory networks for differentiation and pluripotency in embryonic stem (ES) cells have long been suggested to be mutually exclusive. However, with the identification of many new components of these networks ranging from epigenetic, transcriptional, and translational to even post-translational mechanisms, the cellular states of pluripotency and early differentiation might not be strictly bi-modal, but differentiating stem cells appear to go through phases of simultaneous expression of stemness and differentiation genes...
2015: Scientific Reports
Xiaoyu Qu, Jerry Davison, Liping Du, Barry Storer, Derek L Stirewalt, Shelly Heimfeld, Elihu Estey, Frederick R Appelbaum, Min Fang
Aberrant DNA methylation is known to occur in cancer, including hematological malignancies such as acute myeloid leukemia (AML). However, less is known about whether specific methylation profiles characterize specific subcategories of AML. We examined this issue by using comprehensive high-throughput array-based relative methylation analysis (CHARM) to compare methylation profiles among patients in different AML cytogenetic risk groups. We found distinct profiles in each group, with the high-risk group showing overall increased methylation compared with low- and mid-risk groups...
2015: Epigenetics: Official Journal of the DNA Methylation Society
Elisa Cuevas, Agnieszka Rybak-Wolf, Anna M Rohde, Duong T T Nguyen, F Gregory Wulczyn
Lin41/Trim71 is a heterochronic gene encoding a member of the Trim-NHL protein family, and is the original, genetically defined target of the microRNA let-7 in C. elegans. Both the LIN41 protein and multiple regulatory microRNA binding sites in the 3' UTR of the mRNA are highly conserved from nematodes to humans. Functional studies have described essential roles for mouse LIN41 in embryonic stem cells, cellular reprogramming and the timing of embryonic neurogenesis. We have used a new gene trap mouse line deficient in Lin41 to characterize Lin41 expression during embryonic development and in the postnatal central nervous system (CNS)...
2015: Frontiers in Cell and Developmental Biology
Matyas Ecsedi, Magdalene Rausch, Helge Großhans
The let-7 microRNA (miRNA) regulates stemness in animals ranging from worms to humans. However, the cause of the dramatic vulval rupturing phenotype of let-7 mutant C. elegans has remained unknown. Consistent with the notion that miRNAs function by coordinately tuning the expression of many targets, bursting may result from joint dysregulation of several targets, possibly in the epidermis. Alternatively, overexpression of LET-60/RAS, a key vulva development gene and a phylogenetically conserved target of let-7, may be responsible...
February 9, 2015: Developmental Cell
Loris De Cecco, Tiziana Negri, Silvia Brich, Valentina Mauro, Fabio Bozzi, GianPaolo Dagrada, Vittoria Disciglio, Roberta Sanfilippo, Alessandro Gronchi, Maurizio D'Incalci, Paolo G Casali, Silvana Canevari, Marco A Pierotti, Silvana Pilotti
to investigate the events involved in the progression of myxoid liposarcoma (MLS). Gene expression profiling and immunohistochemical/biochemical analyses were applied to specimens representative of the opposite ends of the MLS spectrum: pure myxoid (ML) and pure round cell (RC) liposarcomas. The analyses revealed the involvement of both coding and non coding RNAs (SNORDs located in DLK1-DIO3 region) and support a model of stepwise progression mainly driven by epigenetic changes involving tumour vascular supply and tumoral cellular component...
August 15, 2014: Oncotarget
Hong-Dan Wang, Qiao-Fang Hou, Qian-Nan Guo, Tao Li, Dong Wu, Xian-Ping Zhang, Yan Chu, Miao He, Hai Xiao, Liang-Jie Guo, Ke Yang, Shi-Xiu Liao, Bo-Feng Zhu
BACKGROUND: DNA methylation is a crucial epigenetic modification of the genome which is involved in embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. Consistent with these important roles, DNA methylation has been demonstrated to be required for vertebrate early embryogenesis and essential for regulating temporal and spatial expression of genes controlling cell fate and differentiation. Further studies have shown that abnormal DNA methylation is associated with human diseases including the embryonic development diseases...
2014: BMC Medical Genomics
Seo Hyun Lee, Sungchan Cho, M Sun Kim, Kwangman Choi, Jae Youl Cho, Ho-Shin Gwak, Youn-Jae Kim, Heon Yoo, Seung-Hoon Lee, Jong Bae Park, Jong Heon Kim
let-7 microRNA (miRNA) is implicated in various biological processes, and its downregulation essentially linked to human malignancy. Regulation of gene expression of the let-7 family is critically linked to RNA-binding proteins. For instance, Lin28B and its paralog, Lin28A, inhibit the pre-let-7 precursor from being processed to mature miRNA by recruiting terminal uridyltransferase, TUT4, which adds oligomeric U at the 3' end, suggesting that deregulation of Lin28B, together with Lin28A, may alter various biological processes through modulation of let-7 expression...
May 2014: Biochimica et Biophysica Acta
Kathleen A Worringer, Tim A Rand, Yohei Hayashi, Salma Sami, Kazutoshi Takahashi, Koji Tanabe, Megumi Narita, Deepak Srivastava, Shinya Yamanaka
Reprogramming differentiated cells into induced pluripotent stem cells (iPSCs) promotes a broad array of cellular changes. Here we show that the let-7 family of microRNAs acts as an inhibitory influence on the reprogramming process through a regulatory pathway involving prodifferentiation factors, including EGR1. Inhibiting let-7 in human cells promotes reprogramming to a comparable extent to c-MYC when combined with OCT4, SOX2, and KLF4, and persistence of let-7 inhibits reprogramming. Inhibiting let-7 during reprogramming leads to an increase in the level of the let-7 target LIN-41/TRIM71, which in turn promotes reprogramming and is important for overcoming the let-7 barrier to reprogramming...
January 2, 2014: Cell Stem Cell
S Chul Kwon, Hyerim Yi, Katrin Eichelbaum, Sophia Föhr, Bernd Fischer, Kwon Tae You, Alfredo Castello, Jeroen Krijgsveld, Matthias W Hentze, V Narry Kim
RNA-binding proteins (RBPs) have essential roles in RNA-mediated gene regulation, and yet annotation of RBPs is limited mainly to those with known RNA-binding domains. To systematically identify the RBPs of embryonic stem cells (ESCs), we here employ interactome capture, which combines UV cross-linking of RBP to RNA in living cells, oligo(dT) capture and MS. From mouse ESCs (mESCs), we have defined 555 proteins constituting the mESC mRNA interactome, including 283 proteins not previously annotated as RBPs. Of these, 68 new RBP candidates are highly expressed in ESCs compared to differentiated cells, implicating a role in stem-cell physiology...
September 2013: Nature Structural & Molecular Biology
Thejaswini Venkatesh, Padmanaban S Suresh
P bodies are 100-300 nm sized organelles involved in mRNA silencing and degradation. A total of 60 human proteins have been reported to localize to P bodies. Several human SNPs contribute to complex diseases by altering the structure and function of the proteins. Also, SNPs alter various transcription factors binding, splicing and miRNA regulatory sites. Owing to the essential functions of P bodies in mRNA regulation, we explored computationally the functional significance of SNPs in 7 P body components such as XRN1, DCP2, EDC3, CPEB1, GEMIN5, STAU1 and TRIM71...
October 10, 2013: Gene
Matyas Ecsedi, Helge Grosshans
lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) is well known for being a conserved target of the let-7 (lethal 7) microRNA (miRNA), a regulatory relationship found in animals evolutionarily as distant as Caenorhabditis elegans and humans. It has thus been studied extensively as a model for miRNA-mediated gene silencing. In contrast, the developmental and molecular functions of LIN41 have historically received less attention. However, LIN41 proteins are now emerging as important regulators of cell proliferation and differentiation in stem and progenitor cells...
March 15, 2013: Genes & Development
I Rot, B Kablar
The involvement of skeletal muscle in the process of palatal development in mammals is an example of Waddingtonian epigenetics. Our earlier study showed that the cleft palate develops in the complete absence of skeletal musculature during embryonic development in mice. This contrasts with previous beliefs that tongue obstruction prevents the elevation and fusion of the palatal shelves. We argue that the complete absence of mechanical stimuli from the adjacent muscle, i.e., the lack of both static and dynamic loading, results in disordered palatogenesis...
January 2013: Histology and Histopathology
Inga Loedige, Dimos Gaidatzis, Ragna Sack, Gunter Meister, Witold Filipowicz
TRIM-NHL proteins are conserved regulators of development and differentiation but their molecular function has remained largely elusive. Here, we report an as yet unrecognized activity for the mammalian TRIM-NHL protein TRIM71 as a repressor of mRNAs. We show that TRIM71 is associated with mRNAs and that it promotes translational repression and mRNA decay. We have identified Rbl1 and Rbl2, two transcription factors whose down-regulation is important for stem cell function, as TRIM71 targets in mouse embryonic stem cells...
January 7, 2013: Nucleic Acids Research
Hao-Ming Chang, Natalia J Martinez, James E Thornton, John P Hagan, Khang D Nguyen, Richard I Gregory
Pluripotent embryonic stem cells have a shortened cell cycle that enables their rapid proliferation. The embryonic stem cell-specific miR-290 and miR-302 microRNA families promote proliferation whereas let-7 microRNAs inhibit self-renewal, and promote cell differentiation. Lin28 suppresses let-7 expression in embryonic stem cells. Here to gain further insight into mechanisms controlling embryonic stem cell self-renewal, we explore the molecular and cellular role of the let-7 target Trim71 (mLin41). We show that Trim71 associates with Argonaute2 and microRNAs, and represses expression of Cdkn1a, a cyclin-dependent kinase inhibitor that negatively regulates the G1-S transition...
2012: Nature Communications
Betsy R Maller Schulman, Xianping Liang, Carlos Stahlhut, Casey DelConte, Giovanni Stefani, Frank J Slack
In the nematode Caenorhabditis elegans, the let-7 microRNA (miRNA) controls the timing of key developmental events and terminal differentiation in part by directly regulating lin-41. C. elegans lin-41 mutants display precocious cell cycle exit and terminal differentiation of epidermal skin cells. lin-41 orthologues are found in more complex organisms including both mice and humans, but their roles are not known. We generated Mlin41 mouse mutants to ascertain a functional role for Mlin41. Strong loss of function Mlin41 gene-trap mutants demonstrated a striking neural tube closure defect during development, and embryonic lethality...
December 15, 2008: Cell Cycle
You-Chin Lin, Li-Ching Hsieh, Ming-Wei Kuo, John Yu, Huan-Hsien Kuo, Wan-Lin Lo, Ruey-Jen Lin, Alice L Yu, Wen-Hsiung Li
Animal microRNAs (miRNAs) are short RNAs that function as posttranscriptional regulators of gene expression by binding to the target mRNAs. Noting that some miRNAs are highly conserved in evolution, we explored the possibility of evolutionary conservation of their targets. We identified human orthologues of experimentally verified let-7 miRNA target genes in Caenorhabditis elegans and used the luciferase reporter system to examine whether these human genes are still the targets of let-7 miRNA. We found that in some cases, the miRNA-target relationship has indeed been conserved in human...
November 2007: Molecular Biology and Evolution
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