# Developmental reprogramming and transorganogenesis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA BARBARA · 2023 · $334,325

## Abstract

SUMMARY
The major objectives of the proposed research are to illuminate the cellular and molecular mechanisms that
control developmental plasticity and to investigate how post-mitotic differentiated cells in an intact animal can be
reprogrammed and remodeled into new cell types in the process of transdifferentiation (Td). The well-described
pathway for endoderm development in C. elegans will be applied to molecularly dissecting Td and
“transorganogenesis” (conversion of one organ into another). One component in this pathway, the C. elegans
ELT-7 GATA transcription factor, is capable of converting differentiated, post-mitotic cells of two organs, the
pharynx and uterus, into cells with gene expression patterns and ultrastructural characteristics of normal gut
cells. Highly dynamic changes in the transcriptome occur during this remarkable process, and six stages
(promiscuity, attenuation, extinction, rebound, persistence, and remodeling) can be resolved during Td based
on gene expression and altered cellular and organ morphology. These events define Td-competent (Td+) cells
that convert to gut-like cells and Td-resistant (Td-) cells that only transiently permit ELT-7 to activate its target.
Among the genes whose expression undergoes upregulation during Td are sets of genes associated with protein
turnover, autophagy, and the intracellular pathogen response (IPR), suggesting that these pathways play a role
in Td. On the basis of ELT-7-induced developmental arrest, two genetic selections were developed that identify
large numbers of mutants defective in Td. With these preliminary findings in hand, we will probe the mechanisms
of Td through three Specific Aims. In SA1, we will investigate the dynamics of cellular remodeling, test the
hypothesis that turnover processes of protein degradation and autophagy participate in key stages of Td and
remodeling, assess the role of the IPR in Td, and investigate the action of cell-cycle exit in the Td process. In
SA2, we will evaluate whether differences between single Td+ and Td- cells of varied differentiated cell types can
be ascribed to their unique transcriptome dynamics and will test the hypothesis that changes in chromatin
architecture of Td- cells, assessed by ATAC-seq, initially and transiently proceed through similar patterns to
those of Td+ cells, with elastic reversion to the original state. In SA3, we will characterize mutants from two
genetic selections that are defective in ELT-7-mediated developmental arrest and Td and will use them to
investigate interdependence of the six stages of Td. We will identify the causal gene(s) underlying large numbers
of mutants defective in Td by a high-throughput method based on statistical analysis of variants in pooled
genome-wide sequences, including those coding for proteins and non-coding RNAs. These studies may advance
our understanding of mechanisms involved in pre-cancerous metaplasias of the digestive tract. They will also
provide insights into the mechanis...

## Key facts

- **NIH application ID:** 10588050
- **Project number:** 2R01HD081266-06A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA BARBARA
- **Principal Investigator:** Joel H. Rothman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $334,325
- **Award type:** 2
- **Project period:** 2015-04-01 → 2028-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10588050

## Citation

> US National Institutes of Health, RePORTER application 10588050, Developmental reprogramming and transorganogenesis (2R01HD081266-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10588050. Licensed CC0.

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