# Investigating the role of heterochromatin dynamics to improve functional maturation of stem cell derived pancreatic beta cells

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2020 · $42,147

## Abstract

ABSTRACT
Type 1 diabetes is characterized by destruction of insulin-producing pancreatic beta cells and is one of the most
common metabolic diseases in children (cdc.gov). Current therapies to treat type 1 diabetes include insulin
supplementation and, more recently, transplant of pancreatic islets from deceased donors. However, insulin
treatment is expensive, intrudes on day-to-day life, and can lead to poor glycemic control. Although pancreatic
islet transplantation is more effective at treating diabetes, donor organs are rare and patients must take
immunosuppressive drugs, heightening their risk for infection. To address these therapeutic limitations, protocols
have been established to generate insulin-producing pancreatic beta cells from human pluripotent stem cell
(hPSCs) in vitro. However, hPSC-derived beta cells do not achieve the full functional insulin responsiveness of
their in vivo counterparts in vitro and exhibit a fetal-like phenotype, limiting their usefulness. This data suggests
that some aspects of normal development are not properly recapitulated in vitro systems and that improper gene
regulation leads to expression of lineage inappropriate genes and a reduction in the expression of genes required
for adult function. One mechanism cells use to spatio-temporally restrict gene expression and to permanently
shut down lineage inappropriate genes is by regulating heterochromatin (HC). HC is a structural element of the
mammalian genome associated with methylation of histone 3 lysine (H3K9me3) and characterized by a dense
structure that suppresses gene expression. Four lines of evidence from our lab suggest a strong role of HC
dynamics during cell differentiation and functional maturation. First, analysis of HC state during mouse
embryogenesis revealed a global increase in HC during early development that peaked at germ layer
specification. Subsequent differentiation into liver and pancreatic lineages led to lineage specific decreases in
HC. Second, a comparison of H3K9me3 and sonication resistant condensed heterochromatin (srHC) showed
that 5,632 genes gained and 4,879 genes lost HC compaction between endoderm and mature beta cells during
mouse development. Third, liver lineage specification was perturbed by knockout of 3 H3K9me3 conferring
proteins, and disruption of HC after birth led to defective hepatocyte maturation. Finally, our lab has identified
over 103 HC-associated proteins and has showed that knockdown of 80 of these HC-associated proteins using
an siRNA screen improved direct reprogramming of fibroblasts to a liver lineage. Despite strong evidence for a
role for HC dynamics in fate specification and maturation, the epigenetic mechanisms regulating expression
of beta cell specific genes during functional maturation are unknown. The goal of this proposal is
elucidate the natural dynamics of heterochromatin loss during beta cell maturation in vivo in mice and to use this
information to improve the functional maturation of plu...

## Key facts

- **NIH application ID:** 9988699
- **Project number:** 1F32DK124971-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Alyssa Jane Miller
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $42,147
- **Award type:** 1
- **Project period:** 2020-08-01 → 2021-02-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988699

## Citation

> US National Institutes of Health, RePORTER application 9988699, Investigating the role of heterochromatin dynamics to improve functional maturation of stem cell derived pancreatic beta cells (1F32DK124971-01). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/9988699. Licensed CC0.

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