# Probing the coordination of cell cycle progression and differentiation in hematopoietic stem cells

> **NIH NIH R56** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $538,618

## Abstract

ABSTRACT
Hematopoietic stem cells (HSCs) generate all mature blood cells in adults. They remain quiescent at
homeostasis but when needed, can reenter the cell cycle to either self-renew or differentiate and replenish the
hematopoietic system. While the pathways governing HSC self-renewal are just being uncovered, what
dictates HSC differentiation remains largely elusive. Recent studies indicate that residence in discrete phases
of the cell cycle potentiates differentiation in embryonic and adult stem cells of different origins. However, the
impact of cell cycle residence on HSC differentiation has not been directly explored. Here, we report the
hematopoietic phenotypes elicited upon genetic inactivation of the chromatin modifier Sin3B. Sin3B serves as
a scaffold protein that tethers repressive activities to discrete loci by interacting with sequence-specific
transcription factors and histone modifiers. Through its ability to modulate transcription of cell cycle genes
Sin3B restricts progression through the early phases of the cell cycle. Sin3B-deleted HSCs retain their self-
renewal capacities, but they are unable to properly differentiate. The appropriate expression of lineage
specification transcription factors suggests that alterations of the chromatin landscape likely dictate the
defective differentiation in Sin3B-/- HSCs. Thus, Sin3B inactivation provides a unique opportunity to study the
processes linking cell cycle progression with the generation of a transcriptional environment permissive for
HSC differentiation. Our central hypothesis is that the ability of HSCs to differentiate is restricted to a discrete
window within the early phase of the cell cycle. We will test the possibility that loss of Sin3B induces spurious
progression through early stages of the cell cycle, which is incompatible with proper HSC differentiation, due to
alterations in the chromatin landscape. We propose here to: Establish whether Sin3B-dependent restriction of
cell cycle progression enables HSC differentiation (aim 1). Using cell cycle reporters, lineage tracing tools and
single cell transcriptomic analyses, we will leverage the phenotypes elicited upon Sin3B inactivation to
determine the functional relationship between cell cycle progression and differentiation in HSCs; and
Determine the molecular bases for Sin3B-dependent differentiation in HSCs (aim 2).Through chromatin
accessibility assays and genome-wide mapping of histone marks, we will determine the chromatin features that
enable HSCs to respond to pro-differentiation stimuli during cell cycle progression. Based on our preliminary
data, we will test the hypothesis that specific signaling pathways we found altered in Sin3B-/- HSCs, including
the tonic interferon response, modulate the ability of HSCs to differentiate. Our proposed work will define an
understudied molecular link between cell cycle progression and hematopoietic differentiation, pointing to
potential approaches to modulate HSC expansion and ...

## Key facts

- **NIH application ID:** 10687421
- **Project number:** 1R56HL163940-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Gregory David
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $538,618
- **Award type:** 1
- **Project period:** 2022-09-07 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10687421

## Citation

> US National Institutes of Health, RePORTER application 10687421, Probing the coordination of cell cycle progression and differentiation in hematopoietic stem cells (1R56HL163940-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10687421. Licensed CC0.

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