# Gene Regulatory Mechanisms Controlling Tissue Maturation and Polyploidization

> **NIH NIH R21** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $227,700

## Abstract

I. ABSTRACT
Polyploidy—a state in which cells carry more than two sets of chromosomes—is frequently observed in nature,
yet, the genetic mechanisms controlling ploidy and its functional significance remain enigmatic. The liver, in
particular, gains a high percentage of polyploid hepatocytes during postnatal period of development; and the
frequency and extent of hepatic polyploidization are further increased following injury, DNA damage, and
oxidative stress, but are decreased in hepatocellular carcinoma. Recent evidence suggests that polyploidy
safeguards the liver from tumorigenesis by slowing the proliferative capacity of hepatocytes and maintaining a
reservoir of tumor suppressors. However, there is minimal understanding of the molecular events that govern
the postnatal initiation/promotion of hepatic polyploidization or how differences in chromosomal ploidy affect
the transcriptional and posttranscriptional activities of hepatocytes. We have previously demonstrated that the
RNA binding protein ESRP2 is a key developmentally regulated factor, which activates an adult splicing
program to facilitate terminal differentiation, functional competence, and maturation of hepatocytes. The goals
of this proposal are to (i) determine the physiological necessity/sufficiency of ESRP2 and its splicing-
regulatory-network in driving hepatocyte polyploidy, and (ii) define the quantitative and qualitative impact of
ploidy on hepatocyte transcriptional output. Aim 1 will use ESRP2 gain-and loss-of-function mouse models to
determine if programmed changes in RNA splicing through ESRP2 activation are crucial for the
polyploidization of hepatocytes. In Aim 2, we will generate high-resolution transcriptomes from diploid and
polyploid murine hepatocytes to investigate how ploidy influences the steady-state levels and alternative
splicing patterns of hepatic transcripts at a genome-wide scale. The proposed aims will examine new gene
regulatory mechanism(s) controlling polyploidization while uncovering previously unrecognized links between
alternative splicing and cellular polyploidy.

## Key facts

- **NIH application ID:** 10109241
- **Project number:** 1R21HD104039-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Auinash Kalsotra
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $227,700
- **Award type:** 1
- **Project period:** 2021-04-22 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109241

## Citation

> US National Institutes of Health, RePORTER application 10109241, Gene Regulatory Mechanisms Controlling Tissue Maturation and Polyploidization (1R21HD104039-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10109241. Licensed CC0.

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