# Transcriptional and Epigenetic Control of Pluripotency and Self-Renewal by Honey Bee Royalactin and its human structural analog

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $396,083

## Abstract

Limitations in current treatment options for many congenital and acquired diseases in humans, including
birth defects, cancer, degenerative disorders and diabetes, highlight the need for the development of novel
approaches for regenerative medicine to dramatically improve tissue repair. The pluripotent nature of mammalian
embryonic stem cells (ESCs) makes them a convenient model for studying aspects of early development and
an invaluable starting point for deriving numerous therapeutically relevant cells for regenerative medicine.
Despite the remarkable progress made in deciphering mechanisms driving ESC pluripotency, fundamental gaps
remain in understanding how human embryonic stem cells (hESCs) regulate the pluripotent state. If we are to
use hESCs as a high-fidelity model for embryonic development, and if we wish to improve outcomes of hESC
differentiation and the fidelity of cellular reprogramming to pluripotency, then it is imperative that we understand
how hESCs fit into the paradigm of mammalian embryonic development. In this project we seek to answer some
of these fundamental questions, by characterizing and validating a potential alternative pluripotency state. Our
paradigm-shifting hypothesis stems from our unexpected discovery that the honey bee queen-maker protein,
Royalactin, and its structural analog in mammals, Regina, have unexpected robust pluripotency maintenance
effects in mammalian stem cells. We hypothesize that Regina/Royalactin stabilize and capture a pivotal
pluripotent state distinct from the existing pre- (naïve) and post- (primed) implantation associated stem cell states.
I outline here a plan to molecularly characterize this novel cellular metastable state with 3 specific aims. In Aim
1, we will Isolate and characterize the composition and activity of the receptor complex(es) in ESCs. We
hypothesize that Regina/Royalactin, as secreted molecules, likely directly interact with a receptor partner on the
membrane of responsive cells to affect gene expression and subsequent cellular behavior. We will identify the
receptor(s) through multiple high throughput forward genetics and proteomic strategies. In Aim 2, we will derive
and maintain murine and human ESCs to functionally demonstrate that the Regina/Royalactin-mediated state of
pluripotency can be related back to the signaling pathways involved in lineage specification and maintenance in
the embryo itself. Establishment of a new distinct stage of mammalian pluripotency will be an important advance
in our understanding of early lineage commitment. Lastly, in Aim 3 we will elucidate and characterize the critical
mechanisms that interface between Regina/Royalactin and downstream epigenetic and transcriptomic events.
The genome-wide analyses will be compared to current established conditions to determine whether genetic and
epigenetic instability of the ESCs, associated with impaired developmental potential, exists. Taken together, our
data will directly establish how a novel...

## Key facts

- **NIH application ID:** 10646468
- **Project number:** 5R01GM136737-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Kevin Chun-Kai Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $396,083
- **Award type:** 5
- **Project period:** 2020-08-15 → 2024-01-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10646468

## Citation

> US National Institutes of Health, RePORTER application 10646468, Transcriptional and Epigenetic Control of Pluripotency and Self-Renewal by Honey Bee Royalactin and its human structural analog (5R01GM136737-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10646468. Licensed CC0.

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