# Mechanisms of lineage plasticity revealed by YY1 deficiency.

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $517,821

## Abstract

Hematopoietic development is an ordered process in which stem cells give rise to multiple lineages.
While early progenitors can be multipotent, lineage-specific progenitors reach a stage where they
become exclusively committed to that lineage. For example, B and T cell lineages differentiate from
lymphoid-primed progenitors produced in the bone marrow, and exclusive commitment to the B cell
lineage occurs as cells transition from the pre-pro-B to the pro-B cell stage. Despite the commitment of
pro-B cells to the B lineage, we have made the surprising discovery that conditional knock-out of the
ubiquitous multi-functional transcription factor YY1 in pro-B cells, results in the loss of B lineage
commitment and the consequent ability to develop into the T cell lineage both in vitro and in vivo. To
understand the mechanistic basis for this surprising lineage plasticity, we have developed a new lineage
tracing mouse line that will enable us to determine how YY1-null pro-B cells develop into T lineage cells
(de-differentiation to more primitive progenitors, or trans-differentiation), assess the potential for YY1-
null pro-B cells to develop into other hematopoietic lineages, and determine if YY1-null T cells also
exhibit lineage plasticity (Aim 1). Mechanistically, lineage-specific transcription factors bind to DNA and
regulate gene expression prior to subsequent large-scale alterations in chromatin structure needed for
lineage commitment. Rigorous studies by our laboratory as well as others indicate that despite its
ubiquitous expression pattern, YY1 controls long-range chromatin interactions (LRCIs) in a lineage-
specific fashion. Our findings support the hypothesis that DNA binding by lineage-specific transcription
factors enables YY1 recruitment to distinct genomic loci, thereby enabling YY1 to both generate LRCIs
that stabilize lineage-appropriate gene expression, and to generate repressive chromatin marks
(H3K27me3) at lineage-inappropriate genes. We will thus, compare the molecular genetic phenotype
(gene expression patterns, chromatin accessibility, epigenetic structure, and chromatin folding) of YY1-
null pro-B cells developed into DN1, DN2a, DN2b, DN3, DP, CD4+, and CD8+ T cells, compared to wild-
type T lineage cells, as well as YY1 conditional knockout T lineage cells (Aim 2). We hypothesize that in
the absence of YY1, T lineage development can proceed, but LRCIs needed to stably maintain lineage-
specific gene expression, and heterochromatin needed for repression of alternative lineages will fail to
fully develop, potentially enabling continuing lineage plasticity. Our experiments may reveal a common
mechanism for controlling lineage plasticity, vastly expanding potential applicability of directing YY1-null
cells into multiple lineages.

## Key facts

- **NIH application ID:** 10415006
- **Project number:** 5R01AI162879-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael Lee Atchison
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $517,821
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415006

## Citation

> US National Institutes of Health, RePORTER application 10415006, Mechanisms of lineage plasticity revealed by YY1 deficiency. (5R01AI162879-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10415006. Licensed CC0.

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