# Mechanisms that Regulate Self-renewal and Proliferation in Hematopoietic Stem Cells

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $381,793

## Abstract

It is of critical importance that the rates of hematopoietic stem cell (HSC) differentiation and self-
renewal are carefully regulated and kept in balance, because severe disease states arise when this
balance is disrupted. Unfortunately, the mechanisms that maintain this balance are poorly understood,
and this lack of understanding represents a major impediment to research progress, while also severely
restricting the clinical potential of HSC-based therapeutic interventions. The goal of the research
proposed here is to elucidate mechanisms that regulate HSC quiescence, self-renewal and
differentiation, with a focus on the critical HSC regulatory factor, Yin Yang 1 (YY1). YY1 is a ubiquitous
zinc finger transcription factor that is essential for HSC development in mice. Our recent publication
showed that YY1-deficient HSCs fail to self-renew and fail to maintain a quiescent state. Furthermore,
Stem Cell Factor (SCF)/c-Kit signaling, a critical regulatory pathway in HSC development, is
significantly downregulated in YY1-deficient HSCs. YY1 occupies the distal enhancer and promoter
sequences at the Kit locus and promotes Kit gene expression in HSCs. Thus, our compelling data
implicates the SCF/c-Kit pathway as a critical downstream mediator for YY1 in regulating HSC self-
renewal and quiescence. Our preliminary data also provide strong evidence that YY1-dependent
repression of Structural Maintenance of Chromosomes (SMC) 1 and 3, core components of the cohesin
complex, are critical to its ability to establish quiescence in HSCs. Importantly, defective HSC
quiescence in Yy1 null mice is completely rescued by heterozygosity at Smc3. Collectively, our results
support the hypothesis that YY1 regulates HSC self-renewal and quiescence by mechanisms that
include activation of SCF/c-Kit signaling by controlling chromosome structural change at the Kit locus,
and repression of cohesin. To investigate the hypothesis, an N-terminally truncated YY1 mutant, which
lacks the transcriptional activation and co-activator recruitment functions of YY1, but which retains
transcriptional repression and DNA looping functions of YY1, will be expressed in the bone marrow of
Yy1-/- conditional knockout mice, which allows the YY1 mechanism of action to be evaluated with
respect to SCF/c-Kit signaling, cohesin expression, HSC self-renewal and proliferation. In addition, a
unique Yy1-/- SMC3+/- conditional knockout mouse strain will be used to investigate the mechanism(s)
by which YY1-regulates cohesin and its importance in determining HSC self-renewal and differentiation.
The proposed studies will elucidate as yet poorly characterized mechanisms and pathways in which
YY1 participates and how its effects on HSC cell fate are mediated. These mechanisms are likely to
include YY1-dependent effects on chromatin accessibility, higher-order chromatin/chromosome
structure and/or activation/repression of target genes including Kit and Smc3.

## Key facts

- **NIH application ID:** 10178082
- **Project number:** 5R01HL146540-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** XUAN PAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,793
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10178082

## Citation

> US National Institutes of Health, RePORTER application 10178082, Mechanisms that Regulate Self-renewal and Proliferation in Hematopoietic Stem Cells (5R01HL146540-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10178082. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*