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Overlapping and distinct roles of LIN28 paralogs in reprogramming and stem cell metabolism

ABSTRACT: The RNA binding protein paralogs LIN28A and LIN28B play critical roles in embryonic development, tumorigenesis, and pluripotency. Somatic cells can be reprogrammed to induced pluripotent stem (iPS) cells by overexpression of OCT4 and SOX2 together with NANOG and LIN28A (OSNA), but the exact roles LIN28A/B play are still poorly understood. Here we show that LIN28B likewise promotes reprogramming, and that reactivation of both endogenous LIN28A and B loci are required for maximal reprogramming efficiency. The LIN28B locus has open chromatin and is activated early during reprogramming, whereas LIN28A is activated at later stages by OCT4, marking the transition to bona fide iPS cells. By proteomic and metabolomic analysis, we demonstrate that LIN28A chiefly regulates let-7 and protein translation, whereas LIN28B promotes embryonic metabolism by repressing oxidative phosphorylation and enhancing glycolysis. Thus, LIN28A and LIN28B play independent and cooperative roles in reprogramming and pluripotent stem cell metabolism. 8 samples in total were analyzed. 2 replicates for each phenotypes. Controls are the wild type (flox) without lin28a/b loss of function.

ORGANISM(S): Mus musculus

SUBMITTER: JIN ZHANG

PROVIDER: E-GEOD-66838 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Overlapping and distinct roles of LIN28 paralogs in reprogramming and stem cell metabolism

Project description:The RNA binding protein paralogs LIN28A and LIN28B play critical roles in embryonic development, tumorigenesis, and pluripotency. Somatic cells can be reprogrammed to induced pluripotent stem (iPS) cells by overexpression of OCT4 and SOX2 together with NANOG and LIN28A (OSNA), but the exact roles LIN28A/B play are still poorly understood. Here we show that LIN28B likewise promotes reprogramming, and that reactivation of both endogenous LIN28A and B loci are required for maximal reprogramming efficiency. The LIN28B locus has open chromatin and is activated early during reprogramming, whereas LIN28A is activated at later stages by OCT4, marking the transition to bona fide iPS cells. By proteomic and metabolomic analysis, we demonstrate that LIN28A chiefly regulates let-7 and protein translation, whereas LIN28B promotes embryonic metabolism by repressing oxidative phosphorylation and enhancing glycolysis. Thus, LIN28A and LIN28B play independent and cooperative roles in reprogramming and pluripotent stem cell metabolism.

2015-12-31 | GSE66838 | GEO

Overlapping and distinct roles of LIN28 paralogs

Project description:Lin28a or Lin28b single knockout or double knockout MEF cells reprogrammed to iPS cells Lin28a or Lin28b single knockout or double knockout MEF cells reprogrammed to iPS cells

2016-05-24 | GSE67568 | GEO

Transcriptional program for induced delta cell on day10

Project description:Direct lineage conversion of adult cells is a promising approach for regenerative medicine. A major challenge of lineage conversion is to generate specific subtypes of cells, closely related cells with distinct properties. The pancreatic islets contain three major hormone-secreting endocrine subtypes: insulin+ β-cells, glucagon+ α-cells, and somatostatin+ δ-cells. We previously reported that a combination of three transcription factors, Ngn3, Mafa, and Pdx1, directly reprogram pancreatic acinar cells to β-cells. We now show that acinar cells can be converted to δ-like and α-like cells by Ngn3 and Ngn3+Mafa respectively. Thus, three major islet endocrine subtypes can be derived by acinar reprogramming. Ngn3 promotes establishment of a generic endocrine state in acinar cells at the onset of reprogramming in addition to promoting δ-specification. Mafa and Pdx1 suppress δ-specification in α- and β-cell formation. These studies identify a set of defined factors whose combinatorial actions reprogram acinar cells to distinct islet endocrine subtypes in vivo. induced beta cells samples at day 10 collected for the microarray

2013-11-20 | E-GEOD-52522 | biostudies-arrayexpress

Global gene expression analysis of PB-Oct4.2A.cherry iPS-/-, PB-Oct4.2A.cherry (low) iPS-/- and ES cells

Project description:We have generated iPS cell lines with constitutive Oct4 expression at ES-cell level or 3 times lower. The aim of the experiment was to compare the global gene expression profile between these two cell lines and also between each of them and wild type ES cells. We have analysed two biological replicates of each cell line

2013-04-30 | E-GEOD-45003 | biostudies-arrayexpress

LIN28A interactome analyses in human induced pluripotent stem cell-derived neural progenitor cells

Project description:A single protein can be multifaceted depending on the cellular contexts and interacting molecules. LIN28A is an RNA-binding protein that governs developmental timing, cellular proliferation, differentiation, stem cell pluripotency, and metabolism. In addition to its best-known roles in microRNA biogenesis, diverse molecular roles have been recognized. In the nervous system, LIN28A is known to play critical roles in proliferation and differentiation of neural progenitor cells (NPC). We profiled the endogenous LIN28A-interacting proteins in NPC differentiated from human induced pluripotent stem (iPS) cells using immunoprecipitation and liquid chromatography-tandem mass spectrometry. We identified over 500 LIN28A-interacting proteins, including 156 RNA-independent interactors. Functions of these proteins span a wide range of gene regulatory processes. Our analysis opens multiple avenues for elaborating molecular roles and characteristics of LIN28A.

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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

Generation of parthenogenetic iPS cells from parthenogenetic neural stem cell

Project description:In pluripotential reprogramming, a pluripotent state is established within somatic cells. In this study, we have generated induced pluripotent stem (iPS) cells from bi-maternal (uniparental) parthenogenetic neural stem cells (pNSCs) by transduction with four (Oct4, Klf4, Sox2, and c-Myc) or two (Oct4 and Klf4) transcription factors. The parthenogenetic iPS (piPS) cells directly reprogrammed from pNSCs were able to generate germline-competent himeras, and hierarchical clustering analysis showed that piPS cells were clustered more closer to parthenogenetic ES cells than normal female ES cells. Interestingly, piPS cells showed loss of parthenogenetic-specific imprinting patterns of donor cells. Microarray data also showed that the maternally imprinted genes, which were not expressed in pNSCs, were upregulated in piPS cells, indicating that pluripotential reprogramming lead to induce loss of imprinting as well as re-establishment of various features of pluripotent cells in parthenogenetic somatic cells. 5 samples were analyzed by microarray, each one them in duplicate. fNSC: Mouse female NSC (Neural Stem Cell) pNSC: Mouse parthenogenetic NSC (Neural Stem Cell) piPS-2F: Mouse parthenogenetic induced pluripotent cells derived from NSC overexpressing Oct4 and Klf4 pESC-B: Mouse parthenogenetic ESC (Embryonic Stem Cell) SSEA-1 sorted fESC: Mouse female ESC (Embryonic Stem Cell) OG2

2010-05-20 | E-GEOD-15561 | biostudies-arrayexpress

Identification of mRNAs bound and regulated by human LIN28 proteins and molecular requirements for RNA recognition [Affymetrix]

Project description:Human LIN28A and B are RNA-binding proteins (RBPs) conserved in animals with important roles during development and stem cell reprogramming. We used Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation (PAR-CLIP) in HEK293 cells and identified a largely overlapping set of ~3,000 mRNAs at ~9,500 sites located in the 3M-bM-^@M-^YUTR and CDS. In vitro and in vivo, LIN28 preferentially bound single-stranded RNA containing a uridine-rich element and one or more flanking guanosines, and appeared to be able to disrupt base-pairing to access these elements when embedded in predicted secondary structure. In HEK293 cells, LIN28 protein binding mildly stabilized target mRNAs and increased protein abundance. The top targets were its own mRNAs and those of other RBPs and cell-cycle regulators. Alteration of LIN28 protein levels also negatively regulated the abundance of some, but not all let-7 miRNA family members, indicating sequence-specific binding of let-7 precursors to LIN28 proteins and competition with cytoplasmic miRNA biogenesis factors. To assess whether the transcripts identified by PAR-CLIP are regulated by LIN28B we analyzed the mRNA levels of LIN28B overexpressing and LIN28B-depleted cells using microarrays. Transcripts crosslinked to LIN28B were slightly downregulated upon LIN28B knockdown compared to LIN28B overexpression indicating that LIN28B stabilizes transcripts. The RBP LIN28B was depleted by siRNAs and the expression levels was compared to mock-transfected HEK293 cells The RBP LIN28B was depleted by siRNAs and the expression levels was compared to mock-transfected HEK293 cells

2013-02-26 | E-GEOD-44613 | biostudies-arrayexpress

Identification of mRNAs bound and regulated by human LIN28 proteins and molecular requirements for RNA recognition [RNA-Seq]

Project description:Human LIN28A and B are RNA-binding proteins (RBPs) conserved in animals with important roles during development and stem cell reprogramming. We used Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation (PAR-CLIP) in HEK293 cells and identified a largely overlapping set of ~3,000 mRNAs at ~9,500 sites located in the 3M-bM-^@M-^YUTR and CDS. In vitro and in vivo, LIN28 preferentially bound single-stranded RNA containing a uridine-rich element and one or more flanking guanosines, and appeared to be able to disrupt base-pairing to access these elements when embedded in predicted secondary structure. In HEK293 cells, LIN28 protein binding mildly stabilized target mRNAs and increased protein abundance. The top targets were its own mRNAs and those of other RBPs and cell-cycle regulators. Alteration of LIN28 protein levels also negatively regulated the abundance of some, but not all let-7 miRNA family members, indicating sequence-specific binding of let-7 precursors to LIN28 proteins and competition with cytoplasmic miRNA biogenesis factors. To assess whether miRNAs are regulated by LIN28B we analyzed the miRNA levels of LIN28B overexpressing and LIN28B-depleted cells using small RNA cDNA library sequencing. The RBP LIN28B was depleted by siRNAs and the expression levels was compared to mock-transfected HEK293 cells.

2013-02-26 | E-GEOD-44568 | biostudies-arrayexpress

Gene expression from human fibroblasts

Project description:Since the initial discovery that OCT4, SOX2, KLF4 and c-MYC overexpression sufficed for the induction of pluripotency in somatic cells, methodologies replacing the original factors have enhanced our understanding of the reprogramming process. However, unlike in mouse, OCT4 has not been replaced successfully during reprogramming of human cells. Here we report on a strategy to do so. Through a combination of transcriptome and bioinformatic analysis we have identified factors previously characterized as being lineage specifiers that are able to replace OCT4 and SOX2 in the reprogramming of human fibroblasts. Our results show that is possible to replace OCT4 and SOX2 simultaneously with alternative lineage specifiers in the reprogramming of human cells. At a broader level, they also support a model in which counteracting lineage specification networks underlie the induction of pluripotency, We analyzed 3 arrays from human fibroblats; 1 array from 4F iPSC; 1 array from 4F iPSC; 1 array for GATA3SOX2, KLF4 and cMYC iPS; 1 array for GATA3vP16,SOX2VP16, KLF4 and cMYC iPS;1 array for GATA3vP16SOX2VP16, KLF4 and cMYC iPS; 1 array for GATA3vP16SOX2VP16, KLF4 and cMYC iPS; 1 array for hES4;1 array for hES10; 1 arrays for iPS generated with OCT4, ZIC2, ZNF521, ASCL1, HESX1,FOXD5,KLF4 and cMYC; 1 arrays for iPS generated with OCT4, ZIC2, ZNF521, ASCL1, HESX1,FOXD5,KLF4 and cMYC; 1 array for iPS generated with OCT4, SOX1, KLF4 and cMYC;1 array for iPS generated with OCT4, SOX1, KLF4 and cMYC;1 array for iPS generated with OCT4, ZNF521, KLF4 and cMYC: 1 array for iPS generated with OCT4, SOX3, KLF4 and cMYC

2013-12-31 | E-GEOD-48275 | biostudies-arrayexpress

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