# Driving lymphoid potential in multipotent hematopoietic progenitors by linker histones

> **NIH NIH R56** · YALE UNIVERSITY · 2024 · $560,828

## Abstract

Driving lymphoid potential in multipotent hematopoietic progenitors by linker histones
Abstract
Functionally impaired hematopoietic stem and progenitor cells (HSPCs) often display differentiation skewed
toward the myeloid lineage, underlying disease states such as myeloproliferation, inflammation and cancer1-3.
The molecular mechanisms responsible for the myeloid versus lymphoid decision within the multipotent HSPCs
remains poorly understood, and intervention strategies to boost lymphopoiesis are limited. Chromatin organizes
as DNA wrapping around the core nucleosomes, with linker histones binding to the nucleosome dyad. Linker
histone binding stabilizes nucleosomes, compacts chromatin, reduces accessibility, and is enriched in
heterochromatic regions. We have generated a doxycycline (Dox) inducible H1.0 overexpression transgene
(iH1.0). Using this mouse model, we discovered that H1.0 overexpression in HSPCs leads to dramatically
expanded lymphoid biased and committed progenitors as well as more mature lymphocytes in circulation. Based
on the strong lymphoid differentiation potential of H1.0+ HSPCs, we aim to define a molecular pathway that
regulates the lineage output of multipotent HSPCs by linker histones via three specific aims. Aim 1 will test the
hypothesis that either a specific linker histone isoform, i.e. H1.0, or the abundance of total H1, drive the lymphoid
potential of multipotent HSPCs, by examining the lineage potential of various H1 null and re-expression models.
Aim 2 will address how lineage specificality is accomplished, as H1s do not have sequence specificity. Our
preliminary data show that H1.0 overexpression leads to sharply reduced chromatin accessibility at the Hepatic
Leukemia Factor (Hlf) gene, and reduced Hlf mRNA expression. As Hlf has strong myeloid-promoting effect, we
will test whether linker histone promotes lymphoid potency by restricting chromatin accessibility at this myeloid-
specifying factors to reduce its expression. As our preliminary data show that H1.0 protein undergoes aspartyl
protease-dependent turnover, Aim 3 will test the hypothesis that inhibiting aspartyl proteases prevents the drop
in H1.0 protein and sustains lymphoid differentiation potency. The effects of several inhibitors of the HIV
protease, an aspartyl protease, on the endogenous H1.0 and lymphopoiesis will be examined. This proposal will
yield novel insights on how lymphoid fate specification is controlled by nucleosome/chromatin compaction via
linker histones, and approaches to adjust the hematopoietic lineage output for therapeutic gains.

## Key facts

- **NIH application ID:** 11172039
- **Project number:** 1R56HL173442-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Shangqin Guo
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $560,828
- **Award type:** 1
- **Project period:** 2024-09-17 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11172039

## Citation

> US National Institutes of Health, RePORTER application 11172039, Driving lymphoid potential in multipotent hematopoietic progenitors by linker histones (1R56HL173442-01). Retrieved via AI Analytics 2026-09-03 from https://api.ai-analytics.org/grant/nih/11172039. Licensed CC0.

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