Publications by authors named "Anastasia Kristine Varanko"

4 Publications

  • Page 1 of 1

Radical and lunatic fringes modulate notch ligands to support mammalian intestinal homeostasis.

Elife 2018 04 9;7. Epub 2018 Apr 9.

Center for Genomics and Computational Biology, Department of Biomedical Engineering, Duke University, Durham, United States.

Notch signalling maintains stem cell regeneration at the mouse intestinal crypt base and balances the absorptive and secretory lineages in the upper crypt and villus. Here we report the role of Fringe family of glycosyltransferases in modulating Notch activity in the two compartments. At the crypt base, RFNG is enriched in the Paneth cells and increases cell surface expression of DLL1 and DLL4. This promotes Notch activity in the neighbouring + stem cells assisting their self-renewal. Expressed by various secretory cells in the upper crypt and villus, LFNG promotes DLL surface expression and suppresses the secretory lineage . Hence, in the intestinal epithelium, Fringes are present in the ligand-presenting 'sender' secretory cells and promote Notch activity in the neighbouring 'receiver' cells. Fringes thereby provide for targeted modulation of Notch activity and thus the cell fate in the stem cell zone, or the upper crypt and villus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.35710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896954PMC
April 2018

A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self-renewal.

Mol Syst Biol 2017 04 28;13(4):927. Epub 2017 Apr 28.

School of Electrical and Computer Engineering, Cornell University, Ithaca, NY, USA

The intestinal epithelium is the fastest regenerative tissue in the body, fueled by fast-cycling stem cells. The number and identity of these dividing and migrating stem cells are maintained by a mosaic pattern at the base of the crypt. How the underlying regulatory scheme manages this dynamic stem cell niche is not entirely clear. We stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene. Inactivation of the positive feedback by CRISPR/Cas9 mutation of the binding sequence alters the mosaic stem cell niche pattern and hinders regeneration in organoids. Dynamical system analysis and agent-based multiscale stochastic modeling suggest that the positive feedback enhances the robustness of Notch-mediated niche patterning. This study highlights the importance of feedback mechanisms in spatiotemporal control of the stem cell niche.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408779PMC
http://dx.doi.org/10.15252/msb.20167324DOI Listing
April 2017

A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer.

Cell Stem Cell 2016 Feb;18(2):189-202

School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. Electronic address:

Emerging evidence suggests that microRNAs can initiate asymmetric division, but whether microRNA and protein cell fate determinants coordinate with each other remains unclear. Here, we show that miR-34a directly suppresses Numb in early-stage colon cancer stem cells (CCSCs), forming an incoherent feedforward loop (IFFL) targeting Notch to separate stem and non-stem cell fates robustly. Perturbation of the IFFL leads to a new intermediate cell population with plastic and ambiguous identity. Lgr5+ mouse intestinal/colon stem cells (ISCs) predominantly undergo symmetric division but turn on asymmetric division to curb the number of ISCs when proinflammatory response causes excessive proliferation. Deletion of miR-34a inhibits asymmetric division and exacerbates Lgr5+ ISC proliferation under such stress. Collectively, our data indicate that microRNA and protein cell fate determinants coordinate to enhance robustness of cell fate decision, and they provide a safeguard mechanism against stem cell proliferation induced by inflammation or oncogenic mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stem.2016.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751059PMC
February 2016

miR-1269 promotes metastasis and forms a positive feedback loop with TGF-β.

Nat Commun 2015 Apr 15;6:6879. Epub 2015 Apr 15.

1] School of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA [2] Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA [3] Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, USA.

As patient survival drops precipitously from early-stage cancers to late-stage and metastatic cancers, microRNAs that promote relapse and metastasis can serve as prognostic and predictive markers as well as therapeutic targets for chemoprevention. Here we show that miR-1269a promotes colorectal cancer (CRC) metastasis and forms a positive feedback loop with TGF-β signalling. miR-1269a is upregulated in late-stage CRCs, and long-term monitoring of 100 stage II CRC patients revealed that miR-1269a expression in their surgically removed primary tumours is strongly associated with risk of CRC relapse and metastasis. Consistent with clinical observations, miR-1269a significantly increases the ability of CRC cells to invade and metastasize in vivo. TGF-β activates miR-1269 via Sox4, while miR-1269a enhances TGF-β signalling by targeting Smad7 and HOXD10, hence forming a positive feedback loop. Our findings suggest that miR-1269a is a potential marker to inform adjuvant chemotherapy decisions for CRC patients and a potential therapeutic target to deter metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms7879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399006PMC
April 2015