# Structure of post-replicative chromatin during cell reprogramming in fibrotic disease

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $377,484

## Abstract

Project Summary: Most tissues of the eye are susceptible to developing fibrotic disease, blinding
millions of people throughout the world. There are no effective approaches to prevent, slow or reverse
this disease process. The cell type responsible for causing fibrotic disease is the myofibroblast.
Understanding how a cell acquires an altered heritable phenotype to become a myofibroblast, leading to
scarring associated with this pathological disease process, is a key question, likely to provide essential
clues toward developing anti-fibrotic therapeutics. Changing transcriptional programming during
reprogramming of a cell to a myofibroblast is not well understood. In many aspects, it may rely on
changes in the epigenetic mechanisms of inheritance of chromatin structure during DNA replication. The
mechanism of epigenetic inheritance during cell proliferation remains unknown, and we know even less
about how epigenetic information and the corresponding transcriptional programs change during cell
reprogramming. The gaps in our knowledge of these essential biological processes are based on the
lack of direct experimental approaches that would allow examining the structure of chromatin and the
state of transcription during and following DNA replication during cell proliferation and cell differentiation.
 Using newly developed experimental paradigms, we found that epigenetic marking during cell
proliferation relies not on the transfer of modified histones to daughter strands, but rather on stable
association of multiple histone-modifying proteins during DNA replication. Similar results were obtained
in multiple lens models of cell reprogramming leading to fibrotic disease. Lens cells before injury and until
the first day following surgery in the ex vivo chick model have chromatin that is characterized by a
significant delay in the accumulation of the key repressive histone mark H3K27me3 following DNA
replication. This signifies a de-condensed structure of nucleosomes. The same `open' post-replicative
chromatin was also discovered in mouse and human lens cells during their induction to the myofibroblast
phenotype, suggesting that this is a previously unknown pivotal property of all myofibroblast progenitor
cells. Our data suggests that this `open' state of post-replicative chromatin is more amenable to binding
of newly induced specific transcription factors (TFs) essential for cell reprogramming. Importantly, the
state of `open' chromatin may be manipulated in order to change the ability of TFs to associate with their
target sites on DNA to therapeutically target myofibroblast differentiation. We propose to further examine:
1) The epigenetic mechanisms involved in regulating cell reprogramming to a myofibroblast and 2)
Whether epigenetic mechanisms can be manipulated to alter phenotypic outcome of cell reprogramming
to a myofibroblast. We anticipate that the epigenetic molecular events and anti-fibrotic strategies
discovered from the proposed studies wil...

## Key facts

- **NIH application ID:** 9895805
- **Project number:** 5R01EY026159-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** ALEXANDER M MAZO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $377,484
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895805

## Citation

> US National Institutes of Health, RePORTER application 9895805, Structure of post-replicative chromatin during cell reprogramming in fibrotic disease (5R01EY026159-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9895805. Licensed CC0.

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