# The Role of Mitotic Bookmarking in the Molecular Resetting of the Pluripotent Stem Cell Identity

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $47,269

## Abstract

PROJECT SUMMARY/ABSTRACT
 Understanding how cell fate is maintained or altered during normal development or disease is of
fundamental importance for biomedical research. Mitosis is a period of particular stress on cell identity,
as transcription is halted, transcription factors (TFs) leave the chromatin, and chromatin collapses into a
cell type invariant structure. This poses a challenge for all cycling cells, but in particular for pluripotent
stem cells (PSCs), which proliferate rapidly and must retain the capacity to both self-renew and
differentiate into any somatic cell type. Recent studies reported a partial persistence of selected
epigenetic marks and TFs on mitotic chromatin, a phenomenon known as mitotic bookmarking, and
provided evidence for its importance in stem cell identity maintenance. However, the role and underlying
mechanisms of mitotic bookmarking in the propagation of PSC identity remain elusive. Furthermore, little
is known about the extent or nature of molecular destabilization during mitosis in PSCs, as most existing
information is from somatic cells.
 The long-term goal of this project is therefore to elucidate mechanisms by which PSCs maintain or
change their cell identity. The specific objective is to determine the functional role of mitotic bookmarking
in the inheritance of the stem cell identity after mitosis. Genome-wide assays assessing transcription and
chromatin architecture will be used to characterize the dynamic molecular reestablishment of PSC
identity upon mitotic exit and to determine the extent to which mitotic bookmarking is predictive of faster
resetting (Aim 1). These findings will be functionally validated by utilizing tools to degrade bookmarking
TFs specifically during mitotic exit and then by assessing the consequent changes in molecular resetting
and maintenance of pluripotency (Aim 2). The central hypothesis is that, in PSCs, bookmarking factors
act to prime bookmarked regions to be reset more quickly and faithfully than non-bookmarked regions,
and that the rapid reactivation of these genes (largely stem cell-specific genes) is necessary for the
maintenance of stem cell identity.
 The expected outcome of this project is to reveal the significance of mitotic bookmarking in stem cell
identity and cell fate determination. Successful completion of the aims will provide the knowledge and
impetus to utilize the period of destabilized stem cell identity during mitosis to efficiently generate cell
types of biomedical relevance. It will also provide mechanistic insight into a potential cell-type specific
degree, necessity, and nature of bookmarking. Furthermore, given that dysregulation of cell identity is
responsible for various diseases and malignancies, insights into the driving forces that direct these
aberrant cell identity changes can help to identify new drug targets and therefore possible treatment
options.

## Key facts

- **NIH application ID:** 9926084
- **Project number:** 5F30HD097926-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Bobbie Pelham-Webb
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,269
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926084

## Citation

> US National Institutes of Health, RePORTER application 9926084, The Role of Mitotic Bookmarking in the Molecular Resetting of the Pluripotent Stem Cell Identity (5F30HD097926-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9926084. Licensed CC0.

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