# Setd2 ensures the establishment of a precise basal inflammatory state within murine hematopoietic stem/progenitor cells

## TL;DR

This study shows that Setd2 helps maintain a baseline inflammatory state in blood stem cells, which is crucial for immune function and may impact diseases like MDS.

## Contribution

The study identifies Setd2 as a novel epigenetic amplifier of baseline inflammation in hematopoietic stem/progenitor cells.

## Key findings

- Setd2 ablation eliminates IFN-enriched HSPC subpopulations and reduces inflammatory signaling.
- Setd2-deficient HSPCs show impaired IFNγ responsiveness and reduced B-lymphopoiesis.
- Setd2 sustains chromatin accessibility and enhancer activity at inflammatory gene loci.

## Abstract

The maintenance of a basal immunoinflammatory signature in hematopoietic stem/progenitor cells (HSPCs) constitutes a fundamental regulatory axis governing hematopoietic competence and immune effector generation. While epigenetic repressors constrain this inflammatory phenotype, the molecular amplifiers that preserve this critical state remain undefined. Through integrated single-cell transcriptomic/epigenomic profiling and functional interrogation, we identify Setd2-mediated H3K36me3 as an indispensable epigenetic amplifier sustaining baseline inflammation in murine HSPCs. Setd2 ablation specifically eliminated interferon (IFN)-enriched HSPC subpopulations and attenuated inflammatory signaling cascades. Functionally, Setd2-deficient HSPCs exhibited impaired IFNγ responsiveness, compromised B-lymphopoiesis, and diminished reconstitution capacity due to Lin−c-Kit+Sca1high cell depletion. Paradoxically, Setd2 loss conferred resistance to IFNγ-induced HSPCs exhaustion, which may contribute to the maintenance of Setd2-deficient HSPCs in our myelodysplastic syndrome (MDS) model under the inflammatory milieu. Mechanistically, Setd2 sustained chromatin accessibility and enhancer (H3K27ac) activity at inflammatory gene loci. This work delineates a critical link between Setd2-mediated chromatin regulation, baseline inflammation, HSPC function, and immune competence, providing insights into inflammatory dysregulation in hematopoietic malignancies like MDS.