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Investigating the Mechanisms of in vivo Cellular Reprogramming and Transorganogenesis in Caenorhabditis elegans

  • Author(s): Spickard, Erik Anthony
  • Advisor(s): Rothman, Joel H
  • et al.
Abstract

Cellular reprogramming has the potential to treat numerous degenerative diseases and repair injured organs, but safe and effective therapeutic applications require deeper understanding of the molecular and cellular consequences of forced cell fate changes. The model organism Caenorhabditis elegans can be used to study cellular reprogramming in vivo and features diverse reprogramming-related events, including: the multipotency-to-commitment transition during embryogenesis, naturally occurring transdifferentiation, and forced reprogramming of the germline and differentiated somatic cells. A remarkable finding from a previous study showed that ectopic expression of the transcription factor ELT-7 alone is capable of triggering transdifferentiation of the pharynx into intestine-like tissue, and “transorganogenesis” of the entire uterus into a well-formed intestine-like organ. However, the molecular mechanisms involved in this process are largely unknown.

In this work, I primarily utilize reverse genetic screening and time course mRNA-sequencing methods to probe the ability of ELT-7 to initiate reprogramming and to identify biological processes involved in somatic gonad-to-intestine transorganogenesis. I find that reprogramming to intestine mirrors embryonic endoderm development, engaging most, if not all, of the endoderm gene regulatory network (GRN). Three chromatin-associated factors are identified that appear to be playing important roles in ELT-7-directed transorganogenesis, suggesting that establishment of proper chromatin architecture may define a permissive cellular context for reprogramming into intestine. Bioinformatics analysis of the ELT-7-directed reprogramming temporal transcriptional profile shows that widespread gene expression changes occur even in some non-reprogrammed tissues, indicating significant cell fate elasticity and suggesting cell type-specific modes for cell fate maintenance. Finally, and somewhat surprisingly, gene expression changes following ectopic ELT-7 expression reveal the activation of an intracellular pathogen response (IPR) that correlates both spatially and temporally with cellular reprogramming and may be promoting somatic gonad-to-intestine transorganogenesis.

This work presents the gene expression dynamics of in vivo cellular reprogramming and characterizes the distinct biological processes involved. These findings suggest that the cell type-specific reprogramming ability of ELT-7 may rely on the robust endoderm GRN and require a cellular context that is capable of activating the IPR. These data will enable further targeted research into the mechanisms of transorganogenesis and may lead to the discovery of similar phenomena in C. elegans and other organisms.

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