Sokol Lab
Regulatory RNA pathways in
Stem cells and differentiation
Projects
Overview
The Sokol lab exploits the genetically tractable fly model system to study the heterochronic pathway, which includes the LIN-28 RNA binding protein and the let-7 microRNA and controls stem cell fate and differentiation in response to environmental cues. Broadly conserved across the animal kingdom, LIN-28 is found in large quantities in early embryos and is also present in adult stem cells. In contrast, let-7 and related microRNAs are absent in early stages of animal development but abundant in differentiated cells at later stages. We study the activities of both LIN-28 and let-7 microRNAs within the context of fundamental cell properties (metabolism, reproduction, and identity), with particular attention to their roles in the timing mechanisms that prompt the emergence of specific cell types during development and in response to environmental cues. We take advantage of key strengths of the fly system, including well characterized populations of stems cells that underlie tissue construction, remodeling, and regeneration, a biology that facilitates the integration of detailed biochemical and genetic analyses (including CRISPR-mediated genome editing), and large-scale resources and techniques that enable rapid and comprehensive exploratory screens to identify novel components of conserved genetic pathways. Given that LIN-28 and let-7 microRNAs are also present in humans, we believe that our approach in flies will build a foundation for better understanding the cellular basis of human development, tissue homeostasis and regeneration, and cancer.
Translational control of stem cell behavior
Stem cells switch from asymmetric to symmetric division to expand in number during tissue growth or after injury. The cellular factors that influence this switch are largely unknown, but our recent findings indicates that LIN-28 is a central player in this decision (Chen, 2015). The conserved RNA-binding protein Lin-28 provides a unique entry point into these regulatory RNA pathways, since it is a general stemness factor – abundant in embryonic stem cells and adult stem cells but absent in most differentiated cells – and its elevated but uncharacterized activity enhances tissue regeneration and pluripotent cell programming in mice and human cells, respectively . While an attractive candidate for therapeutic intervention, essential details about the Lin-28 pathway – its mRNA targets, its mechanism of action, its regulation – are currently unknown and, furthermore, not easily determined in available vertebrate system. Because of this, there is a critical need for a genetically tractable in vivo model system that can be used to decipher the Lin-28-related regulatory RNA mechanism that controls adult stem cell behavior. Drosophila offers such a system, providing a proven platform to identify Lin-28 targets and cofactors whose regulation and function can be rigorously and rapidly characterized at the cellular level. Because the behavior of fly and human stem cells are remarkably similar, such analysis should illuminate fundamental principles of stem cell behavior underlying tissue homeostasis and regeneration in animals including humans.
microRNAs in stem cell fate and differentiation
The let-7 and miRNA-125 microRNAs regulate stem cell identity and differentiation and are deregulated in human diseases, including cancer. In flies and vertebrate systems, let-7 and miRNA-125 are co-transcribed with each other and a third miRNA, miRNA-100, from a single locus, termed the let-7- Complex (let-7-C) (Sokol et al., 2008). Despite intensive investigation of the molecular mechanisms controlling microRNA biogenesis, the regulation and processing of polycistronic microRNA transcripts like that produced by let-7-C has received comparatively little attention. Combining the strengths of the fly as a premier genetic and biochemical model system, the Sokol lab has established methods to identify novel regulators of let-7-C microRNA production and activity (Chawla and Sokol, 2012, 2014; Luhur et al., 2014) as well as analyze the role of these factors in controlling stem cell identity and differentiation in vivo (Wu et al., 2012). Our future studies will define the molecular mechanisms that modulate miRNAs in order to control stem cell behavior during development and adulthood and in response to environmental cues.
Uncovering microRNA pathways
Using a large-scale genetic approach to screen for mutations that affect expression of a joint let-7 and miR- 125 reporter transgene, we recovered mutations in ~100 different genes (see Luhur et al., 2014 for a description of methods). Analysis of a subset of these has identified novel properties of known microRNA regulators as well as new microRNA regulators. We will now use biochemical and molecular methods to distinguish whether identified factors affect let-7 and/or miRNA-125 production or activity. In addition, in vivo genetic analysis will determine the role of these factors in neural stem cell differentiation. Finally, we will map, clone and characterize the remaining alleles identified from the screen, many of which are homozygous viable, using a novel mapping scheme we recently developed in collaboration with Dr. Kevin Cook (Bloomington Drosophila Stock Center).
Our recent papers
Opposing Post-transcriptional Control of InR by FMRP and LIN-28 Adjusts Stem Cell-Based Tissue Growth.
Arthur Luhur, Kasun Buddika, Ishara Ariyapala, Shengyao Chen, and Nick Sokol
Cell Reports. 2017 Dec 5:21(10):2671-2677.
PMID: 29212015
A let-7-to-miR-125 MicroRNA Switch Regulates Neuronal Integrity and Lifespan in Drosophila.
Geetanjali Chawla, Padmini Deosthale, Sue Childress, Yen-Chi Wu and
Nick Sokol
PLoS Genet. 2016 Aug 10;12(8):e1006247. doi: 10.1371/journal.pgen.1006247. eCollection 2016 Aug.
Neural stem cell-encoded temporal patterning delineates an early window of malignant susceptibility in Drosophila.
Karine Narbonne-Reveau, Elodie Lanet, Caroline Dillard, Sophie Foppolo, Ching-Huan Chen, Hugues Parrinello, Stéphanie Rialle, Nicholas Sokol, and Cédric Maurange
eLife. 2016 Jun 14;5. pii: e13463. doi: 10.7554/eLife.13463. PMID: 27296804
Starving for more: Nutrient sensing by LIN-28 in adult intestinal progenitor cells.
Arthur Luhur and Nick Sokol
Fly (Austin). 2016 Mar 2:0, [Epub ahead of print]
Lin-28 promotes symmetric stem cell division and drives adaptive growth in the adult Drosophila intestine.
Ching-huan chen, arthur luhur and nick sokol
Development. 2015 Oct 15;142(20):3478-87. PMID: 26487778
ADAR mediates differential expression of polycistronic microRNAs
geetanjali chawla and nick sokol
Nucleic Acids Research 2014 Apr;42(8):5245-55. PMID: 24561617
Drosha-independent DGCR8/Pasha pathway regulates neuronal morphogenesis.
Arthur luhur, geetanjali chawla, yen-chi wu, jing li and nick sokol
Proceedings of the National Academy of Sciences, 2014 Jan 28;111(4):1421-6. PMID: 24474768
MicroRNAs as components of systemic signaling pathways in Drosophila melanogaster.
Arthur luhur, geetanjali chawla, and nick sokol
Current Topics in Developmental Biology, 2013;105:97-123.
PMID: 23962840
Let-7-complex microRNAs regulate the temporal identity of Drosophila mushroom body neurons via chinmo.
Yen-chi wu, ching-huan chen, adam mercer, and nick sokol
Developmental Cell, 2012 Jul 17;23(1):202-9. PMID: 22814608
Small temporal RNAs in animal development.
Nick Sokol
Current Opinion in Genetics and Development, 2012 Aug;22(4):369-73 PMID: 22578317
Hormonal activation of let-7-C microRNAs via EcR is required for adult Drosophila melanogaster morphology and function.
geetanjali chawla and nick sokol
Development. 2012 May;139(10):1788-97. PMID: 22510985
The role of microRNAs in muscle development.
Nick Sokol
Current Topics in Developmental Biology, 2012;99:59-78.
PMID: 22365735
MicroRNAs in Drosophila development.
Geetanjali chawla and nick sokol
International Review in Cell and Molecular Biology, 2011;286:1-65.
PMID: 21199779
Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression.
Stephan gehrke, yuzuru imai, nick sokol and bingwei lu
Nature. 2010 Jul 29;466(7306):637-41. PMID: 20671708
Drosophila let-7 microRNA is required for remodeling of the neuromusculature during metamorphosis.
nick Sokol, peizhang xu, yuh nung jan, and victor ambros
Genes and Development. 2008 Jun 15:22(12):1591-6.
PMID: 18559475
Who we are
Ishara Ariyapala
Graduate Student
BS University of Colombo
Madelyn Beck
Undergraduate Researcher
Kasun Buddika
Graduate Student
BS University of Colombo
Mary Ann Hazuga
Undergraduate Researcher
Sromana Mukherjee
Graduate Student
MS University of Calcutta
BS St. Xavier's College
Sam Norrell
Undergraduate Researcher
Rowan Tansey
Stockkeeper
BA Indiana University
Lab Alumni
And where they are now
Postdoctoral Fellow /Research Scientist
2008-2014
Ching-Huan Chen
Graduate Student
2010-2016
Padmini Deosthale
Graduate Student
2013-2016
Brandon Gutierrez
Graduate Student
2015-2016
Where we are
Jordan Hall A502, Indiana University, Bloomington Indiana
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August 9, 2018December 11, 2017September 2, 2017Get in touch!
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