scholarly journals Identification of PAX6 and NFAT4 as the transcriptional regulators of lncRNA Mrhl in neuronal progenitors

2021 ◽  
Author(s):  
Debosree Pal ◽  
Sangeeta Dutta ◽  
Dhanur P Iyer ◽  
Utsa Bhaduri ◽  
Satyanarayana Manchanahalli Rangasw Rao
Keyword(s):  
Radial Glia ◽  
Embryonic Stem ◽  
Proximal Promoter ◽  
Major Site ◽  
Major Lineage ◽  
Neuronal Progenitor ◽  
Neuronal Progenitors ◽  
Development And Differentiation ◽  
Neuronal Lineage ◽  
Distal Promoter

LncRNA Mrhlhas been shown to be involved in regulating meiotic commitment of mouse spermatogonial progenitors and coordinating differentiation events in mouse embryonic stem cells. Here we have characterized the interplay of Mrhlwith lineage-specific transcription factors during mouse neuronal lineage development. Our results demonstrate that Mrhl is predominantly expressed in the neuronal progenitor populations in mouse embryonic brains and in retinoic acid derived radial-glia like neuronal progenitor cells. Mrhl levels are significantly down regulated in postnatal brains and in maturing neurons. In neuronal progenitors, a master transcription factor, PAX6, acts to regulate the expression of Mrhl through direct physical binding at a major site in the distal promoter, located at 2.9kb usptream of the TSS of Mrhl. Furthermore, NFAT4 occupies the Mrhl proximal promoter at two sites, at 437bp and 143bp upstream of the TSS. ChIP studies reveal that PAX6 and NFAT4 interact with each other, suggesting co-regulation of lncRNA Mrhl expression in neuronal progenitors. Our studies herewith are crucial towards understanding how lncRNAs are regulated by major lineage-specific TFstowardsdefining specific development and differentiation events.

scholarly journals Evidence for an Integrated Gene Repression Mechanism Based on mRNA Isoform Toggling in Human Cells

2018 ◽  
Author(s):  
Ina Hollerer ◽  
Juliet C. Barker ◽  
Victoria Jorgensen ◽  
Amy Tresenrider ◽  
Claire Dugast-Darzacq ◽  
...  
Keyword(s):  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Open Reading Frames ◽  
Proximal Promoter ◽  
Embryonic Stem Cell Differentiation ◽  
Transcriptional Interference ◽  
Upstream Open Reading Frames ◽  
Regulate Protein ◽  
Distal Promoter ◽  
Mrna Isoform

ABSTRACTWe recently described an unconventional mode of gene regulation in budding yeast by which transcriptional and translational interference were used in an integrated manner to down-regulate protein expression. Developmentally timed transcriptional interference inhibited production of a well translated mRNA isoform and resulted in the production of an mRNA isoform containing inhibitory upstream open reading frames (uORFs) that blocked translation of the ORF. Transcriptional interference and uORF-based translational repression are established mechanisms outside of yeast, but whether this type of integrated regulation was conserved was unknown. Here we find that, indeed, a similar type of regulation occurs at the locus for the human oncogene MDM2. We observe evidence of transcriptional interference between the two MDM2 promoters, which produce a poorly translated distal promoter-derived uORF-containing mRNA isoform and a well-translated proximal promoter-derived transcript. Down-regulation of distal promoter activity markedly up-regulates proximal promoter-driven expression and results in local reduction of histone H3K36 trimethylation. Moreover, we observe that this transcript toggling between the two MDM2 isoforms naturally occurs during human embryonic stem cell differentiation programs.

scholarly journals SNAP to attention: A SNARE complex regulates neuronal progenitor polarity

2020 ◽  
Vol 220 (1) ◽  
Author(s):  
Victor Tarabykin
Keyword(s):  
Cell Polarity ◽  
Radial Glia ◽  
Snare Complex ◽  
Membrane Targeting ◽  
Neuronal Progenitor ◽  
Neuronal Progenitors ◽  
Cell Biol ◽  
Polarity Establishment ◽  
Adherence Junction

SNARE vesicle targeting complex controls the polarity of neuronal progenitors. Kunii et al. (2020. J. Cell Biol. https://doi.org/10.1083/jcb.201910080) show that the SNAP23–VAMP8–Syntaxin1B complex is required for membrane targeting of N-cadherin and formation of adherence junction complexes in radial glia neuronal progenitors, the major prerequisite of cell polarity establishment.

Dppa2/4 as a trigger of signaling pathways to promote zygote genome activation by binding to CG-rich region

2020 ◽  
Author(s):  
Hanshuang Li ◽  
Chunshen Long ◽  
Jinzhu Xiang ◽  
Pengfei Liang ◽  
Xueling Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathways ◽  
Embryonic Stem ◽  
Proximal Promoter ◽  
Human Embryos ◽  
Double Knockout ◽  
Rich Region ◽  
Induced Pluripotent ◽  
Zygote Genome Activation ◽  
Genome Activation

Abstract Developmental pluripotency-associated 2 (Dppa2) and developmental pluripotency-associated 4 (Dppa4) as positive drivers were helpful for transcriptional regulation of zygotic genome activation (ZGA). Here, we systematically assessed the cooperative interplay of Dppa2 and Dppa4 in regulating cell pluripotency and found that simultaneous overexpression of Dppa2/4 can make induced pluripotent stem cells closer to embryonic stem cells (ESCs). Compared with other pluripotency transcription factors, Dppa2/4 can regulate majorities of signaling pathways by binding on CG-rich region of proximal promoter (0–500 bp), of which 85% and 77% signaling pathways were significantly activated by Dppa2 and Dppa4, respectively. Notably, Dppa2/4 also can dramatically trigger the decisive signaling pathways for facilitating ZGA, including Hippo, MAPK and TGF-beta signaling pathways and so on. At last, we found alkaline phosphatase, placental-like 2 (Alppl2) was completely silenced when Dppa2 and 4 single- or double-knockout in ESC, which is consistent with Dux. Moreover, Alppl2 was significantly activated in mouse 2-cell embryos and 4–8 cells stage of human embryos, further predicted that Alppl2 was directly regulated by Dppa2/4 as a ZGA candidate driver to facilitate pre-embryonic development.

scholarly journals Developmental regulation of lck gene expression in T lymphocytes.

1991 ◽  
Vol 173 (2) ◽  
pp. 383-393 ◽  
Author(s):  
R S Wildin ◽  
A M Garvin ◽  
S Pawar ◽  
D B Lewis ◽  
K M Abraham ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Short Interval ◽  
T Antigen ◽  
Lymphoid Cells ◽  
Proximal Promoter ◽  
Large T Antigen ◽  
Sv40 Large T Antigen ◽  
Promoter Sequences ◽  
Antigen Gene ◽  
Distal Promoter

In the mouse and human, mRNA transcripts encoding the lymphocyte-specific protein tyrosine kinase p56lck are derived from two separate promoters resulting in heterogeneity in the 5' untranslated region sequence. The proximal promoter lies just 5' to the coding region for the gene and is active only in thymocytes. In contrast, the distal promoter lies 34 kilobases (kb) 5' in the human, and is active both in thymocytes and mature peripheral T cells. As previously reported, transgenic mice bearing functional proximal promoter sequence juxtaposed with the SV40 large T antigen gene invariably develop lymphoid tumors confined to the thymus. In the current work, transgenic mice bearing a 2.6-kb fragment of the human distal promoter fused to the SV40 large T antigen gene express large T antigen in thymocytes and in peripheral lymphoid cells, and develop tumors of both the thymus and the peripheral lymphoid organs. The ability of the human distal promoter to function appropriately in transgenic mice is consistent with the strong similarity observed between the mouse and human distal promoter sequences. With the exception of a single short interval that serves as a target for binding of nuclear factors, significant sequence similarity is not seen when the distal and proximal promoter sequences are compared. Hence, developmentally regulated, lineage-specific transcription of the lck gene is mediated by distinct promoter sequences that appear to be capable of functioning independently.

scholarly journals Epsins Regulate Mouse Embryonic Stem Cell Exit from Pluripotency and Neural Commitment by Controlling Notch Activation

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Marina Cardano ◽  
Jacopo Zasso ◽  
Luca Ruggiero ◽  
Giuseppina Di Giacomo ◽  
Matteo Marcatili ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Notch Signaling ◽  
Neural Differentiation ◽  
Radial Glia ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Neural Progenitors ◽  
Notch Activation

Epsins are part of the internalization machinery pivotal to control clathrin-mediated endocytosis. Here, we report that epsin family members are expressed in mouse embryonic stem cells (mESCs) and that epsin1/2 knockdown alters both mESC exits from pluripotency and their differentiation. Furthermore, we show that epsin1/2 knockdown compromises the correct polarization and division of mESC-derived neural progenitors and their conversion into expandable radial glia-like neural stem cells. Finally, we provide evidence that Notch signaling is impaired following epsin1/2 knockdown and that experimental restoration of Notch signaling rescues the epsin-mediated phenotypes. We conclude that epsins contribute to control mESC exit from pluripotency and allow their neural differentiation by appropriate modulation of Notch signaling.

scholarly journals Three-Dimensional Otic Neuronal Progenitor Spheroids Derived from Human Embryonic Stem Cells

2020 ◽  
Author(s):  
Rachel A. Heuer ◽  
Kevin T. Nella ◽  
Hsiang-Tsun Chang ◽  
Kyle S. Coots ◽  
Andrew M. Oleksijew ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Neuronal Progenitor

Characterization Of a Weakly Expressed KIR2DL1 Allele

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4847-4847
Author(s):  
Hongchuan Li ◽  
Andrew R Huehn ◽  
Postbaccalaureate Fellow ◽  
Paul W Wright ◽  
Research Biologist ◽  
...  
Keyword(s):  
Single Copy ◽  
Surface Expression ◽  
Genetic Alterations ◽  
Proximal Promoter ◽  
Nucleotide Polymorphisms ◽  
Coding Region ◽  
Class I Mhc ◽  
Complete Sequencing ◽  
Weak Expression ◽  
Distal Promoter

Abstract The variegated expression of the human KIR family of class I MHC receptors provides an interesting model system for the study of stochastic activation of gene transcription. Previous studies have linked distal KIR promoter transcription to the initiation of KIR expression from the proximal promoter. In order to identify novel genetic alterations associated with decreased KIR expression, a group of 182 donors was characterized for KIR gene content, KIR transcripts, and FACS analysis of KIR surface expression. An individual was discovered that possessed a single copy of the KIR2DL1 gene but had a low level of gene expression by either FACS or Q-PCR.  Complete sequencing of the KIR2DL1 gene confirmed the presence of an intact coding region. Analysis of promoter elements revealed a cluster of three single nucleotide polymorphisms (SNPs) in the distal promoter approximately 1 kb upstream from the start of KIR2DL1 translation. These SNPs are also found in the distal promoter region of the non-transcribed KIR2DL5*002 allele as well as the KIR3DP1 pseudogene. One of these SNPs creates a functional binding site for the ZEB1 transcription factor.  Individuals possessing the ZEB1 site in their KIR2DL1 promoter produce high levels of a non-translatable distal KIR2DL1transcript that inhibits transcription from the proximal promoter, resulting in weak expression of this allele. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Funded by NCI Contract HHSN261200800001E. Disclosures: Miller: Coronado Biosciences: Scientific Advisory Board Other.

scholarly journals Differentiation of pluripotent embryonic stem cells into the neuronal lineage in vitro gives rise to mature inhibitory and excitatory neurons

1995 ◽  
Vol 53 (2) ◽  
pp. 275-287 ◽  
Author(s):  
Carsten Strübing ◽  
Gudrun Ahnert-Hilger ◽  
Jin Shan ◽  
Bertram Wiedenmann ◽  
Jürgen Hescheler ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Excitatory Neurons ◽  
Neuronal Lineage

scholarly journals The E3 Ligase Axotrophin/MARCH-7: Protein Expression Profiling of Human Tissues Reveals Links to Adult Stem Cells

2009 ◽  
Vol 58 (4) ◽  
pp. 301-308 ◽  
Author(s):  
Cristina A. Szigyarto ◽  
Paul Sibbons ◽  
Gill Williams ◽  
Mathias Uhlen ◽  
Su M. Metcalfe
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Protein Expression ◽  
Adult Stem Cells ◽  
Embryonic Stem ◽  
Cell Types ◽  
Null Mouse ◽  
Specific Cell ◽  
Direct Role ◽  
Neuronal Progenitor

Axotrophin/MARCH-7 was first identified in mouse embryonic stem cells as a neural stem cell gene. Using the axotrophin/MARCH-7 null mouse, we discovered profound effects on T lymphocyte responses, including 8-fold hyperproliferation and 5-fold excess release of the stem cell cytokine leukemia inhibitory factor (LIF). Our further discovery that axotrophin/MARCH-7 is required for targeted degradation of the LIF receptor subunit gp190 implies a direct role in the regulation of LIF signaling. Bioinformatics studies revealed a highly conserved RING-CH domain in common with the MARCH family of E3-ubiquitin ligases, and accordingly, axotrophin was renamed “MARCH-7.” To probe protein expression of human axotrophin/MARCH-7, we prepared antibodies against different domains of the protein. Each antibody bound its specific target epitope with high affinity, and immunohistochemistry cross-validated target specificity. Forty-eight human tissue types were screened. Epithelial cells stained strongly, with trophoblasts having the greatest staining. In certain tissues, specific cell types were selectively positive, including neurons and neuronal progenitor cells in the hippocampus and cerebellum, endothelial sinusoids of the spleen, megakaryocytes in the bone marrow, crypt stem cells of the small intestine, and alveolar macrophages in the lung. Approximately 20% of central nervous system neuropils were positive. Notably, axotrophin/MARCH-7 has an expression profile that is distinct from that of other MARCH family members. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.

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