Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Int J Mol Sci ; 21(5)2020 Mar 10.
Article in English | MEDLINE | ID: mdl-32164275

ABSTRACT

Traumatic brain injury is known to reprogram the epigenome. Chromatin immunoprecipitation-sequencing of histone H3 lysine 27 acetylation (H3K27ac) and tri-methylation of histone H3 at lysine 4 (H3K4me3) marks was performed to address the transcriptional regulation of candidate regeneration-associated genes. In this study, we identify a novel enhancer region for induced WNT3A transcription during regeneration of injured cortical neurons. We further demonstrated an increased mono-methylation of histone H3 at lysine 4 (H3K4me1) modification at this enhancer concomitant with a topological interaction between sub-regions of this enhancer and with promoter of WNT3A gene. Together, this study reports a novel mechanism for WNT3A gene transcription and reveals a potential therapeutic intervention for neuronal regeneration.


Subject(s)
Brain Injuries, Traumatic/genetics , Histones/metabolism , Neurons/physiology , Wnt3A Protein/genetics , Acetylation , Animals , Brain Injuries, Traumatic/metabolism , Chromatin Immunoprecipitation , Disease Models, Animal , Enhancer Elements, Genetic , Epigenesis, Genetic , Methylation , Neurons/metabolism , Promoter Regions, Genetic , Rats , Rats, Sprague-Dawley , Regeneration
3.
Elife ; 72018 10 12.
Article in English | MEDLINE | ID: mdl-30311912

ABSTRACT

The mammalian imprinted Dlk1-Dio3 locus produces multiple long non-coding RNAs (lncRNAs) from the maternally inherited allele, including Meg3 (i.e., Gtl2) in the mammalian genome. Although this locus has well-characterized functions in stem cell and tumor contexts, its role during neural development is unknown. By profiling cell types at each stage of embryonic stem cell-derived motor neurons (ESC~MNs) that recapitulate spinal cord development, we uncovered that lncRNAs expressed from the Dlk1-Dio3 locus are predominantly and gradually enriched in rostral motor neurons (MNs). Mechanistically, Meg3 and other Dlk1-Dio3 locus-derived lncRNAs facilitate Ezh2/Jarid2 interactions. Loss of these lncRNAs compromises the H3K27me3 landscape, leading to aberrant expression of progenitor and caudal Hox genes in postmitotic MNs. Our data thus illustrate that these lncRNAs in the Dlk1-Dio3 locus, particularly Meg3, play a critical role in maintaining postmitotic MN cell fate by repressing progenitor genes and they shape MN subtype identity by regulating Hox genes.


When a gene is active, its DNA sequence is 'transcribed' to form a molecule of RNA. Many of these RNAs act as templates for making proteins. But for some genes, the protein molecules are not their final destinations. Their RNA molecules instead help to control gene activity, which can alter the behaviour or the identity of a cell. For example, experiments performed in individual cells suggest that so-called long non-coding RNAs (or lncRNAs for short) guide how stem cells develop into different types of mature cells. However, it is not clear whether lncRNAs play the same critical role in embryos.Yen et al. used embryonic stem cells to model how motor neurons develop in the spinal cord of mouse embryos. This revealed that motor neurons produce large amounts of a specific group of lncRNAs, particularly one called Meg3. Further experiments showed that motor neurons in mouse embryos that lack Meg3 do not correctly silence a set of genes called the Hox genes, which are crucial for laying out the body plans of many different animal embryos. These neurons also incorrectly continue to express genes that are normally active in an early phase of the stem-like cells that make motor neurons.There is wide interest in how lncRNAs help to regulate embryonic development. With this new knowledge of how Meg3 regulates the activity of Hox genes in motor neurons, research could now be directed toward investigating whether lncRNAs help other tissues to develop in a similar way.


Subject(s)
Cell Lineage , Genetic Loci , Intercellular Signaling Peptides and Proteins/genetics , Iodide Peroxidase/genetics , Mitosis , Motor Neurons/cytology , Motor Neurons/metabolism , RNA, Long Noncoding/metabolism , Animals , Base Sequence , Calcium-Binding Proteins , Cell Differentiation/genetics , Cell Lineage/genetics , Cell Nucleus/metabolism , Cervical Vertebrae/innervation , Embryo, Mammalian/metabolism , Epigenesis, Genetic , Gene Expression Regulation, Developmental , Genomic Imprinting , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Mice , Mitosis/genetics , Mutation/genetics , Phenotype , RNA, Long Noncoding/genetics
4.
Cell Rep ; 11(8): 1305-18, 2015 May 26.
Article in English | MEDLINE | ID: mdl-26004179

ABSTRACT

Motor neurons (MNs) are unique because they project their axons outside of the CNS to innervate the peripheral muscles. Limb-innervating lateral motor column MNs (LMC-MNs) travel substantially to innervate distal limb mesenchyme. How LMC-MNs fine-tune the balance between survival and apoptosis while wiring the sensorimotor circuit en route remains unclear. Here, we show that the mir-17∼92 cluster is enriched in embryonic stem cell (ESC)-derived LMC-MNs and that conditional mir-17∼92 deletion in MNs results in the death of LMC-MNs in vitro and in vivo. mir-17∼92 overexpression rescues MNs from apoptosis, which occurs spontaneously during embryonic development. PTEN is a primary target of mir-17∼92 responsible for LMC-MN degeneration. Additionally, mir-17∼92 directly targets components of E3 ubiquitin ligases, affecting PTEN subcellular localization through monoubiquitination. This miRNA-mediated regulation modulates both target expression and target subcellular localization, providing LMC-MNs with an intricate defensive mechanism that controls their survival.


Subject(s)
MicroRNAs/metabolism , Motor Neurons/metabolism , PTEN Phosphohydrolase/metabolism , Animals , Apoptosis/physiology , Mice , Mice, Knockout , MicroRNAs/genetics , Motor Neurons/cytology , Motor Neurons/enzymology , PTEN Phosphohydrolase/genetics , Signal Transduction , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...