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Genome-wide analysis of skeletal muscle gene expression in Lin28A Tg mice

ABSTRACT: To identify mechanisms involved in growth and glucose metabolism, we performed whole genome mRNA expression analysis in five week old quadraceps muscle from 2 CD-1 background male Lin28A Tg and 2 WT littermates (all male) in which there was 7 fold overexpression of Lin28A, a RNA binding protein that enhances Igf2 translation and suppresses the let-7 microRNA biogenesis. Total RNA was harvested and processed using RNeasy mini kits from Qiagen. All RNA samples were DNase treated. The Illumina Ref-8 microarray platform was used to generate data.

ORGANISM(S): Mus musculus

SUBMITTER: Hao Zhu

PROVIDER: E-GEOD-21226 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies.

Zhu Hao H Shah Samar S Shyh-Chang Ng N Shinoda Gen G Einhorn William S WS Viswanathan Srinivas R SR Takeuchi Ayumu A Grasemann Corinna C Rinn John L JL Lopez Mary F MF Hirschhorn Joel N JN Palmert Mark R MR Daley George Q GQ

Nature genetics 20100530 7

Recently, genome-wide association studies have implicated the human LIN28B locus in regulating height and the timing of menarche. LIN28B and its homolog LIN28A are functionally redundant RNA-binding proteins that block biogenesis of let-7 microRNAs. lin-28 and let-7 were discovered in Caenorhabditis elegans as heterochronic regulators of larval and vulval development but have recently been implicated in cancer, stem cell aging and pluripotency. The let-7 targets Myc, Kras, Igf2bp1 and Hmga2 are ...[more]

PMID: 20512147

Similar Datasets

Genome-wide analysis of skeletal muscle gene expression in Lin28A Tg mice

Project description:To identify mechanisms involved in growth and glucose metabolism, we performed whole genome mRNA expression analysis in five week old quadraceps muscle from 2 CD-1 background male Lin28A Tg and 2 WT littermates (all male) in which there was 7 fold overexpression of Lin28A, a RNA binding protein that enhances Igf2 translation and suppresses the let-7 microRNA biogenesis.

2010-04-07 | GSE21226 | GEO

LIN28A binds to meiotic gene transcripts and modulates their translation in male germ cells

Project description:The RNA-binding protein LIN28A is required for maintaining tissue homeostasis, including in the reproductive system, but the underlying mechanisms on how LIN28A regulates germline progenitors remain unclear. Here, we dissected LIN28A-binding targets using high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) in the mouse testes. LIN28A preferentially binds to mRNA coding sequence (CDS) or 3'UTR regions at sites enriched wiGAG(A) sequences. Further investigation of Lin28a null mouse testes indicated that meiosis-associated mRNAs bound by LIN28A were differentially expressed. Next, ribosome profiling revealed that the mRNA levels of these targets were significantly reduced in polysome fractions, and their protein expression levels decreased in the Lin28a null mouse testes, even when meiotic arrest in the null mouse testes was not apparent. Collectively, these findings provide a set of LIN28A-regulated target mRNAs, and show that LIN28A binding might be mechanism through which LIN28A acts to regulate undifferentiated spermatogonia fates and male fertility in mammals.

2020-06-08 | GSE134033 | GEO

RNA-Seq for LIN28A or LIN28A loss of function mutant expressing 293FT cells

Project description:We report the upregulated genes by the expression of LIN28A or loss of function mutant of LIN28A for 293FTcells..

2023-01-11 | GSE174387 | GEO

CLIP-Seq for LIN28A or LIN28A loss of function mutant expressing 293FT cells

Project description:We report the direct target genes by LIN28A or loss of function mutant of LIN28A for 293FTcells using CLIP-Seq

2023-01-11 | GSE174388 | GEO

Expression profiling in LIN28A, SET7/9, and TUT4 depleted H9 cells, or in the silent mutations (siR) of LIN28A and LIN28A-K135R overexpressed H9 cells

Project description:A developmentally regulated RNA binding protein, LIN28A and its homolog LIN28B may share a similar mechanism to regulate the processing of let-7 microRNAs (miRNAs) in embryonic stem cells (ESCs) or certain cancer cells, although their predominant localization is different in cells. However, little is known about the regulatory mechanism of LIN28A for miRNA processing in the nucleus. Here, we show that SET7/9, a known histone methyltransferase, associates with LIN28A in vivo and in vitro. SET7/9-mediated methylation significantly leads to the nuclear retention and protein stability of LIN28A, and remarkably regulated RNA binding ability of LIN28A to pri-let-7. Using RNAi knockdown approach, we find that the methylated nuclear form of LIN28A may function in the nucleoli by sequestering the primary let-7 miRNA to block their processing through a Tut4 (Zcchc11)-independent mechanism to regulate human ESC pluripotency. We propose a new insight toward the understanding of the molecular mechanism for post-translational methylation of nuclear LIN28A along modulating pluripotency by regulating pri-let-7 miRNAs in human ESCs.

2016-12-05 | GSE53038 | GEO

Lin28A binds active promoters and recruits Tet1 to regulate gene expression

Project description:Lin28, a well-known RNA-binding protein, regulates diverse cellular properties. All physiological functions of Lin28A characterized so far have been attributed to its repression of let-7 miRNA biogenesis or modulation of the mRNA translational efficiency. Here we show that Lin28A directly binds to a consensus DNA sequence in vitro and in mouse embryonic stem cells in vivo. ChIP-seq and RNA-seq reveal the enrichment of Lin28A binding around transcription start sites, and a positive correlation between its genomic occupancy and expression of many associated genes. Mechanistically, Lin28A recruits 5-methylcytosine-dioxygenase Tet1 to genomic binding sites to orchestrate 5-methylcytosine and 5-hydroxymethylcytosine dynamics. Either Lin28A or Tet1 knockdown leads to dysregulated DNA methylation and expression of common target genes. These results reveal a surprising role for Lin28A in transcriptional regulation via epigenetic DNA modifications and provide a new framework for understanding mechanisms underlying versatile functions of Lin28A in mammalian systems. Examine the DNA binding ability of Lin28 and its roles in regulating gene expression by coordinating with Tet1

2015-12-07 | E-GEOD-74254 | biostudies-arrayexpress

Lin28A Overexpression Triggers Inflammatory Response in Mouse Kidneys

Project description:The RNA-binding proteins Lin28A and Lin28B play critical roles in regulating gene expression through distinct mechanisms, including the inhibition of Let-7 microRNA maturation and direct mRNA binding. Predominantly expressed in pluripotent and multipotent stem cells, Lin28A and Lin28B contribute to a variety of biological processes such as development, growth, and tissue regeneration. Dysregulation of Lin28A/B expression is associated with numerous types of tumors. In this study, we demonstrate that overexpression of Lin28A in the mouse nephrons leads to severe inflammation and kidney damage, rather than to tumorigenesis. To investigate the causal relationship between kidney damage and inflammation, we utilized steroid treatment to suppress inflammation. This treatment also ameliorated the kidney damage phenotype, indicating that Lin28A overexpression directly induces inflammation, which in turn leads to kidney damage. Notably, Lin28A overexpression causes inflammation only when expressed in nephrons, but not in the stromal cells of the kidneys, highlighting its cell context-dependent nature. The nephron-specific, Lin28A-induced inflammatory response is distinct from the previously described Lin28B-mediated inflammatory feedback loops, as it is not IL-6 dependent. Instead, it is associated with the rapid upregulation of cytokines such as CXCL1 and CCL2. Overall, this study reveals that the impact of abnormal Lin28A expression is broader than previously understood, demonstrating that Lin28A overexpression also plays a role in inflammatory responses. Furthermore, this transgenic mouse model offers a valuable tool for advancing our understanding of the pathophysiology of acute kidney injury (AKI), where inflammation is a key factor.

2024-07-16 | GSE254805 | GEO

LIN28A-mediated regulation of microRNA biogenesis in mouse embryonic stem cell (A3-1) [Agilent]

Project description:LIN28A is a highly-conserved RNA-binding protein which is known to be involved in embryonic development, stem cell maintenance and proliferation. LIN28A is expressed in various types of cancer, and they are associated with advanced tumor malignancy. In embryonic stem cell, LIN28A specifically binds to let-7 precursors to suppress biogenesis of the let-7 microRNA family. In addition, LIN28A was reported to bind several mRNAs such as Oct4, cyclin A/B and histone H2A to activate their translation. For comprehensive understanding of the interaction between LIN28A and their target RNAs, we exploited UV-crosslinking and immunoprecipitation (CLIP) to capture their in vivo binding to target RNAs. LIN28A-binding RNAs were identified in a mouse embryonic stem cell line using multiple monoclonal and polyclonal antibodies. The result shows that LIN28 preferentially binds to let-7 precursors through GGAG binding motif, which is consistent with our previous results. We also identified that LIN28A binding is enriched in a certain subset of mRNAs. To understand the function of the novel LIN28A-mRNA binding, we carried out ribosome profiling from LIN28A-depleted mouse embryonic stem cells. Examination of miRNA level in embryonic stem cell treated with siRNA for GFP or for Lin28a

2012-10-25 | E-GEOD-37112 | biostudies-arrayexpress

Transcriptome-wide identification of LIN28A targets in mouse embryonic stem cell (A3-1) [Illumina Seq]

Project description:LIN28A is a highly-conserved RNA-binding protein which is known to be involved in embryonic development, stem cell maintenance and proliferation. LIN28A is expressed in various types of cancer, and they are associated with advanced tumor malignancy. In embryonic stem cell, LIN28A specifically binds to let-7 precursors to suppress biogenesis of the let-7 microRNA family. In addition, Lin28 was reported to bind several mRNAs such as Oct4, cyclin A/B and histone H2A to activate their translation. For comprehensive understanding of the interaction between LIN28A and their target RNAs, we exploited UV-crosslinking and immunoprecipitation (CLIP) to capture their in vivo binding to target RNAs. LIN28A-binding RNAs were identified in a mouse embryonic stem cell line using multiple monoclonal and polyclonal antibodies. The result shows that LIN28A preferentially binds to let-7 precursors through GGAG binding motif, which is consistent with our previous results. We also identified that LIN28A binding is enriched in a certain subset of mRNAs. To understand the function of the novel LIN28A-mRNA binding, we carried out ribosome profiling from LIN28A-depleted mouse embryonic stem cells. Examination of RNA binding of LIN28A and translation in mouse embryonic stem cell.

2012-10-25 | E-GEOD-37111 | biostudies-arrayexpress

Seizure-induced LIN28A disrupts pattern separation via aberrant hippocampal neurogenesis

Project description:Prolonged seizures can disrupt stem cell behavior in the adult hippocampus, an important brain structure for spatial memory. Here, using a mouse model of pilocarpine-induced status epilepticus (SE), we characterized spatiotemporal expression of Lin28a mRNA and proteins after SE. Unlike Lin28a transcripts, induction of LIN28A protein after SE was detected mainly in the subgranular zone, where immunoreactivity was found in progenitors, neuroblasts, and immature and mature granule neurons. To investigate roles of LIN28A in epilepsy, we generated Nestin-Cre::Lin28aloxP/loxP (cKO) and Nestin-Cre::Lin28a+/+ (WT) mice to block LIN28A upregulation in all neuronal lineages after acute seizure. Adult-generated neuron- and hippocampus-associated cognitive impairments were absent in epileptic LIN28A cKO mice as evaluated by pattern separation and contextual fear conditioning tests, respectively, while sham-manipulated WT and cKO animals showed comparable memory function. Moreover, numbers of hilar PROX1-expressing ectopic granule cells (EGCs), together with PROX1/NEUN+ mature EGCs, were significantly reduced in epileptic cKO mice. Transcriptomic analysis and immunohistochemical validation at 3 d post-pilocarpine provided potential LIN28A downstream targets such as serotonin receptor 4. Collectively, our findings indicate that LIN28A is a novel target for regulation of newborn neuron-associated memory dysfunction in epilepsy by modulating seizure-induced aberrant neurogenesis.

2024-01-01 | GSE246519 | GEO

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