Steven Zvi Josefowicz
Weill Medical College of Cornell University, NY·Microbiology & Immunology
When the body fights an infection, immune cells must switch on inflammatory genes quickly and at the right strength. Too weak a response lets pathogens win; too strong a response damages tissue.
- Fields
Microbiology & Immunology
Genetics
Biochemistry
- Topics
histone variant H3.3
H3f3a
H3f3b
- Grants
- 1 known grant, through Jun 2030
What they work on
- Test whether H3.3 dosage tunes inflammatory gene transcription, immune cell function and pathogen control, using mice with 0–4 copies of H3f3a/H3f3b, mixed bone marrow chimeras and Listeria, Aspergillus and Plasmodium infections.
- Identify the enhancers and transcription factors that control cell-type-specific and stimulation-induced expression of H3f3a and H3f3b, using single-cell enhancer prediction, genetic mouse models and CRISPRi perturbation assays.
- Determine how H3.3 regulates RNA polymerase II pause-release, co-transcriptional splicing and histone modification patterns, using PRO-seq and ChIP-exo mapping at nucleotide resolution.
- Map which H3.3 residues and modifications matter for inflammatory gene expression and macrophage activation through a mutagenesis screen in primary macrophages.
More about the research
This project asks how cells set that strength, focusing on H3.3, a variant form of the histone proteins that package DNA. The lab previously found that H3.3 and its phosphorylation (an added phosphate tag) are needed for rapid transcription of inflammatory genes, especially in macrophages and germinal center B cells. Macrophages are immune cells that engulf microbes; germinal center B cells are antibody-making cells that mature during an immune response. The team also found that H3.3 levels rise and fall during inflammation in both humans and mice.
Why it matters
Inflammation drives damage in many infections and diseases. By showing how the amount of a single DNA-packaging protein sets the strength of immune gene activity, this work could reveal control points for dialing inflammation up or down. It may also clarify why immune responses differ between disease states. Findings in mouse infection models could eventually inform ways to tune harmful or insufficient immune responses.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Laura Banaszynski
University of Texas Southwestern Medical Center, TX·Genetics
Determine how phosphorylation of the histone variant H3.3 at its unique serine stimulates p300, an enzyme that acetylates histones, to produce the enhancer mark H3K27ac in mouse embryonic stem cells.
Jia Fei
Rutgers University-New Brunswick, NJ·Biochemistry
Characterize how NDF loosens nucleosomes, the protein spools that package DNA, and helps RNA Polymerase II move through them, using ultra-high-resolution optical tweezers and cryo-electron microscopy.
Ramiro Verdun
University of Miami, FL·Biochemistry
Determine how bypass of transcription-blocking DNA lesions by RNA Polymerase II, the enzyme that copies genes into RNA, disrupts the cellular response to ultraviolet radiation damage and disturbs normal cell function.
The school
Weill Medical College of Cornell University: 35 labs on PI Pages, $1.6B a year on research, 59 research doctorates a year.
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