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HSC-Mediated Immune Crosstalk in the Bone Marrow

Award Number: F31HL186643
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/17/2026
PERIOD OF PERFORMANCE END DATE: 12/16/2027

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HSC-Mediated Immune Crosstalk in the Bone Marrow - PROJECT SUMMARY Hematopoietic stem cells (HSCs) are defined by their capacity for self-renewal and multilineage differentiation, sustaining blood production throughout life. To maintain long-term self-renewal and prevent exhaustion, adult HSCs reside in a metabolically quiescent state within the bone marrow (BM) niche—an immune-privileged environment that protects them from oxidative stress and immune-mediated damage. Emerging studies reveal that, beyond their classical role, HSCs can shape the immune-protective BM niche by acting as antigen- presenting cells: they express MHC-II molecules and directly engage CD4⁺ T cells. These MHC-II–TCR interactions polarize naïve CD4⁺ T cells to immunosuppressive subsets and reinforce immune tolerance in the niche. Notably, MHC-II expression in HSCs correlates with enhanced long-term self-renewal and balanced lineage output, yet the molecular mechanisms regulating this noncanonical HSC–T cell crosstalk remain incompletely understood. This proposal aims to investigate the epigenetic and chromatin-based mechanisms that govern MHC-II expression and BM T cell interactions by HSCs, with a focus on the Polycomb Group (PcG) protein Yin Yang 1 (YY1). YY1 is a ubiquitously expressed transcription factor and PcG protein that recruits PcG proteins through its REPO domain. Preliminary data show that YY1 PcG function deletion impairs HSC antigen presentation gene expression, reduces MHC-II surface levels, enriches inflammation, and compromises HSC long-term self-renewal. CUT&Tag reveals YY1 binding sites across the MHC-II loci, half of which overlap with chromatin regulators CTCF and/or SMC3, suggesting that YY1 contributes to MHC-II gene regulation via structural chromatin remodeling. Based on these findings, the central hypothesis is that YY1-dependent PcG mechanisms regulate histone modification and chromatin accessibility at MHC-II loci and promote MHC-II expression, thereby facilitating HSC–T cell immune crosstalk and sustaining immune suppression within the BM niche. This proposal outlines two aims: Aim 1. Define how YY1 regulates HSPC-mediated antigen presentation and CD4+ T cell polarization in the BM niche. Aim 2. Determine the mechanisms by which YY1 and its interacting chromatin structural regulators control the chromatin landscape at MHC-II loci. Leveraging advanced chromatin profiling, innovative experimental models, and immunological assays, this work will provide critical insights into how HSCs actively sustain the immune-privileged bone marrow microenvironment. These findings have broad implications for therapeutic strategies targeting BM failure, hematologic malignancies, and transplantation outcomes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $37,544 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Blood Diseases and Resources Research	000	1	6/19/2026	NEW	$37,544
														Subtotal = $37,544

Grand Total All Awards = $37,544

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HSC-Mediated Immune Crosstalk in the Bone Marrow

Award Number: F31HL186643

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/17/2026

PERIOD OF PERFORMANCE END DATE: 12/16/2027

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