# BACH1 as a novel pioneer repressor in macrophages: impact on homeostasis and inflammation

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $550,706

## Abstract

PROJECT SUMMARY
Transcription plays an oversized role in determining proper inflammatory response in immune cells such as
macrophages (MF). Transcriptional master regulators of MFs are thought to be the main drivers of chromatin
reprogramming during myeloid cell differentiation, polarization and activation. However, recent studies have
expanded this “developmental TF-centric” model and suggest that signal-dependent TFs, in particular
repressors, likely to have a pioneer role in the shaping the MF epigenome. Such an expanded model also
predicts that active transcriptional repression and chromatin bookmarking by signal-dependent master
regulators is a key mechanism for the safeguarding the enhancer repertoire and proper deployment and
resolution of an inflammatory response. Recently, we identified such a signal-dependent TF, the heme-
regulated repressor BACH1 (BTB Domain and CNC Homolog 1), with properties of a master regulator of the MF
epigenome. Our preliminary data is contrary to current dogma about this TF and also challenging the
current view of inflammatory gene regulation. The central hypothesis of this proposal is that BACH1 acts
as a pioneering repressor, signal-dependent master regulator and an epigenomic safeguard that plays
a key role during macrophage differentiation and polarization/specification by actively repressing
enhancers, genome-wide, controlling inflammatory, metabolic and differentiation-specific genes with effects on
the baseline, amplitude and proper kinetics of the inflammatory gene expression. We propose three interrelated
and integrated but independent Specific Aims in which we will combine new genetic mouse models with cutting
edge molecular biology approaches to establish BACH1 as a critical modulator of MF inflammatory gene
expression and subtype specification. Our approaches aim to provide deep mechanistic insights on BACH1
function on active repression, pioneering, transcriptional activation, 3D chromatin structure and inflammatory
gene expression and establish BACH1 as a novel signal-dependent master regulator and as part of the core
hardwired transcriptional circuit of MFs. Moreover, results from the proposed work are expected to push the field
forward by providing a mechanistic framework of how heme, a molecule vital for life and cell metabolism but
cytotoxic when in excess, can affect the differentiation and inflammatory potential of MFs.

## Key facts

- **NIH application ID:** 10954329
- **Project number:** 1R01AI185363-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Laszlo Nagy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $550,706
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10954329

## Citation

> US National Institutes of Health, RePORTER application 10954329, BACH1 as a novel pioneer repressor in macrophages: impact on homeostasis and inflammation (1R01AI185363-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10954329. Licensed CC0.

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