# The Role of the De-condensed Structure of Nascent Chromatin During  T Cell Differentiation

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $653,648

## Abstract

Project Summary:
 During cell differentiation, transcriptional programs are changed, and then must be maintained in
turn. Chromatin-based epigenetic mechanisms are at the core of maintenance and switching of
transcriptional programs. The fundamental issues of the nature of epigenetic marking and of the
mechanisms that switch this marking during differentiation remain unclear due to lack of relevant
experimental approaches. We developed new experimental paradigms that allow investigating the
structure of chromatin during DNA replication at a single-cell and at a gene-specific levels. Using our new
techniques, we found striking differences in the structure of chromatin during differentiation of the
pluripotent human embryonic stem cells (hESC) and the antigen-inexperienced (naïve) T cells. During
the first several hours after induction of differentiation of hESCs to dopamine neuron lineage, or T cells to
different T cell subsets, accumulation of H3K27me3 is significantly delayed on nascent DNA. Since the
occurrence of H3K27me3 in the genome coincides with the dense structure of nucleosomes, this
suggests the existence of a temporarily de-condensed structure of nucleosomes on nascent DNA shortly
after induction of cell differentiation. Our preliminary data indicate that the de-condensed, `open' structure
of chromatin may be essential for recruitment to DNA of the lineage-specific transcription factors (TFs)
that are essential to induce changes in transcriptional programs during cell differentiation. Thus, our
results present a molecular explanation of how the vast areas of the repressed genome can be activated
during cell differentiation. The goals of this proposal are to test two unique hypotheses using different
models of differentiation to various lineages for pluripotent hESCs and for specialized T cells: 1) To
examine whether the period of `open' post-replicative chromatin in early differentiating cells is a result of
complex interplay of activities of several histone-modifying proteins; and 2) To examine whether this
open post-replicative chromatin creates a `window of opportunity' for high accessibility of lineage-
specifying TFs that are required to change the transcriptional program during cell differentiation.
Examining these unique hypotheses may provide a universal chromatin-based molecular mechanism for
biological plasticity of the cell.

## Key facts

- **NIH application ID:** 9849158
- **Project number:** 5R01AI125650-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** LORRAINE IACOVITTI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $653,648
- **Award type:** 5
- **Project period:** 2017-02-03 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849158

## Citation

> US National Institutes of Health, RePORTER application 9849158, The Role of the De-condensed Structure of Nascent Chromatin During  T Cell Differentiation (5R01AI125650-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9849158. Licensed CC0.

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