Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

L1 retrotransposition in neurons is mediated by MeCP2

ABSTRACT: L1 retrotransposons are active elements in the genome, capable of mobilization in neuronal progenitor cells. Previously, we showed that chromatin remodeling during neuronal differentiation allows for a transient stimulation of L1 transcription. The activity of L1 retrotransposons during brain development can impact gene expression and neuronal function. Here we show that L1 neuronal retrotransposition in rodents is increased in the absence of MeCP2, a protein involved in global methylation and human neurodevelopmental diseases. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, we revealed that Rett syndrome patients, with MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Our data demonstrate that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition, thereby increasing brain-specific genetic mosaicism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE21037 | GEO | 2010/11/11

SECONDARY ACCESSION(S): PRJNA126459

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

L1 retrotransposition in neurons is mediated by MeCP2

Project description:L1 retrotransposons are active elements in the genome, capable of mobilization in neuronal progenitor cells. Previously, we showed that chromatin remodeling during neuronal differentiation allows for a transient stimulation of L1 transcription. The activity of L1 retrotransposons during brain development can impact gene expression and neuronal function. Here we show that L1 neuronal retrotransposition in rodents is increased in the absence of MeCP2, a protein involved in global methylation and human neurodevelopmental diseases. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, we revealed that Rett syndrome patients, with MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Our data demonstrate that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition, thereby increasing brain-specific genetic mosaicism. Genetic reprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells, or iPSCs) by over-expression of specific genes has been accomplished for fibroblasts derived from controls and Rett syndrome patients. Different clones from each were compared to respective original fibroblasts and a human embryonic stem cell line. Gene expression profiles measured using human genome Affymetrix Gene Chip arrays were grouped by hierarchical clustering, and correlation coefficients were computed for all pair-wise comparisons.

2010-11-11 | E-GEOD-21037 | biostudies-arrayexpress

TDP-43 safeguards the embryo genome from L1 retrotransposition

Project description:We report that TAR DNA binding protein 43 (TDP-43), mutations in which constitute a major risk factor for amyotrophic lateral sclerosis (ALS), inhibits L1 retrotransposition in mouse embryonic stem cells (mESCs) and preimplantation embryos. Knockdown of TDP-43 resulted in massive genomic L1 expansion and impaired cell growth in preimplantation embryos and ESCs. Functional analysis demonstrated that TDP-43 interacts with L1 open reading frame 1 protein (L1 ORF1p) to mediate genomic protection, and loss of this interaction led to de-repression of L1 retrotransposition. Our results identify TDP-43 as a guardian of the embryonic genome by protecting it from massive L1 retrotransposition.

2023-01-04 | GSE199197 | GEO

Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution

Project description:Somatic L1 retrotransposition events have been shown to occur in epithelial cancers1-8. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases, but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds and many were present in multiple tumor sections implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth. Here we show Human SNP 6.0 Array experiments on DNAs from four colorectal cancer patients (1BV, 2BV, 3BV, and 4BV) with polyps and metastases. Here we characterize the samples for CNVs and compare the samples' CNV status to their respective somatic L1 retrotransposition profile.

2015-08-10 | E-GEOD-63601 | biostudies-arrayexpress

Somatic L1 Retrotransposition of Colorectal Tumors

Project description:Somatic L1 Retrotransposition of Colorectal Tumors

| PRJNA173389 | ENA

Pharmacological reversal of synaptic and network pathology in human MECP2-KO neurons and cortical organoids

Project description:Duplication or deficiency of the X-linked MECP2 gene reliably produces profound neurodevelopmental impairment. MECP2 mutations are almost universally responsible for Rett syndrome (RTT), and particular mutations and cellular mosaicism of MECP2 may underlie the spectrum of RTT symptomatic severity. No clinically approved treatments for RTT are currently available, but human pluripotent stem cell technology offers a platform to identify neuropathology and test candidate therapeutics. Using a strategic series of increasingly complex human stem cell-derived technologies, including human neurons, MECP2-mosaic neurospheres to model RTT female brain mosaicism, and cortical organoids, we identified synaptic dysregulation downstream from knockout of MECP2 and screened select pharmacological compounds for their ability to treat this dysfunction. Two lead compounds, Nefiracetam and PHA 543613, specifically reversed MECP2-knockout cytologic neuropathology. The capacity of these compounds to reverse neuropathologic phenotypes and networks in human models supports clinical studies for neurodevelopmental disorders in which MeCP2 deficiency is the predominant etiology.

2020-10-27 | GSE160146 | GEO

L1 retrotransposition in human iPSCs

Project description:Assessing L1 retrotransposition events in human iPSCs through deep sequencing.

| PRJEB6145 | ENA

Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution

Project description:Somatic L1 retrotransposition events have been shown to occur in epithelial cancers1-8. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases, but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds and many were present in multiple tumor sections implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth. We assessed the impact of somatic L1 insertions on the expression of the corresponding protein-coding genes by comparing protein abundance in the polyp with the highest number of somatic L1 insertions with that of its paired normal colon using mass spectrometry analysis. Of the 10 validated somatic insertions that were in protein coding regions in the polyp, two proteins – KIAA1217 and WARS2 – were downregulated in the adenoma >90% and >70%, respectively.

2015-08-11 | PXD001626 | Pride

Transcription profiling of human differentiated vs. undifferentiated SH-SY5Y cells transfected with a MeCP2 (transcriptional repressor) decoy to investigate the neurodevelopmental disorder Rett syndrome

Project description:Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG-binding protein 2. MeCP2 is a transcriptional repressor elevated in mature neurons and is predicted to be required for neuronal maturation by regulating multiple target genes. Identifying primary gene targets in either Mecp2-deficient mice or human RTT brain has proven to be difficult, perhaps because of the transient requirement for MeCP2 during neuronal maturation. In order to experimentally control the timing of MeCP2 expression and deficiency during neuronal maturation, human SH-SY5Y cells undergoing mature neuronal differentiation were transfected with methylated MeCP2 oligonucleotide decoy to disrupt the binding of MeCP2 to endogenous targets. Genome-wide expression microarray analysis identified all four known members of the inhibitors of differentiation or inhibitors of DNA-binding (ID1, ID2, ID3 and ID4) subfamily of helix-loop-helix genes as novel neuronal targets of MeCP2. Chromatin immunoprecipitation analysis confirmed binding of MeCP2 near or within the promoters of ID1, ID2 and ID3, and quantitative RT-PCR confirmed increased expression of all four Id genes in Mecp2-deficient mouse brain. All four ID proteins were significantly increased in Mecp2-deficient mouse and human RTT brain using immunofluorescence and laser scanning cytometric analyses. Because of their involvement in cell differentiation and neural development, ID genes are ideal primary targets for MeCP2 regulation of neuronal maturation that may explain the molecular pathogenesis of RTT.

2007-10-26 | E-GEOD-4600 | biostudies-arrayexpress

Homo sapiens

Project description:L1 retrotransposition in neurons is mediated by MeCP2

| PRJNA126459 | ENA

Widespread endogenous retrotransposition generates somatic genetic mosaicism during human development

Project description:Widespread endogenous retrotransposition generates somatic genetic mosaicism during human development

| PRJEB9178 | ENA