Understanding the lipid link to gene expression in the nucleus

Proteins often get credit for doing all the work to relay messages in cells. But, lipids and sugars act as critical messengers too, helping turn genes on and off. When these nonprotein signals go awry, the consequences can include cancer, diabetes and developmental diseases. Ray Blind wants to know why.

Ray Blind

Blind, an associate professor of cancer research at the Vanderbilt–Ingram Cancer Center in the Department of Medicine at Vanderbilt and a member of the Journal of Lipid Research editorial board, investigates how ligands bind and change the activity of two nuclear receptor 5A, or NR5A, family members called steroidogenic factor-1, or SF-1, and liver receptor homomlog-1, or LRH-1. These receptors help regulate processes that are vital for human health — including reproduction, hormone production and metabolism — making them central to understanding and potentially someday treating a wide range of diseases.

Blind recently discussed his research during ASBMB Breakthroughs, a webinar series featuring work from American Society for Biochemistry and Molecular Biology journals and sponsored by JLR. By dissecting the molecular mechanisms behind nonprotein nuclear signaling, Blind hopes to uncover how gene regulation goes awry in disease and how to fix it.

Looking for lipid ligands

Credit: Ray Blind

A structural model of bilirubin, which Ray Blind and team showed can bind to “orphan” receptor LRH-1.

Both SF-1 and LRH-1 rely on what Blind calls a “steric switch,” a structural change triggered by ligand binding. This conformational shift affects the recruitment of coregulators, altering gene expression.

“Because of this allosteric switch mechanism, these are really popular for drug design because they have a druggable ligand binding pocket,” Blind said.

Building on the work of biochemist Marion Sewer — for whom the ASBMB Marion B. Sewer Distinguished Scholarship for Undergraduates is named — Blind’s team used fluorescence anisotropy to track lipid interactions with SF-1. This method uses polarized light to analyze molecular interactions in solution.

They found that sphingomyelin and ceramide bound more tightly to SF-1 than lysosphingomyelin and sphingosine. This binding strength affected the recruitment of a transcription coregulator called DAX-1. Tighter-binding ceramide enhanced DAX-1 recruitment, while weaker-binding sphingosine did not.

DAX-1 and SF-1 coordinate adrenal and reproductive development, so understanding how ligands influence their interaction can shed light on how they work together to regulate these processes.

In contrast, LRH-1 was long considered an “orphan” receptor without any clear ligands. Recently, using a ligand screen, Blind’s team discovered that bilirubin, a byproduct of heme metabolism, binds LRH-1 and alters its interactions with transcriptional coregulators. 

In liver and kidney human cell lines, bilirubin selectively regulated gene expression and notably downregulated cholesterol metabolism. Blind’s group is continuing to investigate the link between this heme byproduct and cholesterol synthesis to understand the implications for human disease.

Credit: Ray Blind

Ray Blind and colleagues previously published an integrative structure of LRH-1 (with different domains shown in cyan and orange) bound to DNA (atom sticks), phospholipid (white and red sticks) and a transcriptional coactivator peptide.

Controlling genes via lipid modification

Another area of focus for Blind is the enzyme inositol polyphosphate multikinase, or IPMK, which phosphorylates nuclear lipids called phosphoinositides. Blind has been looking for the link between IPMK and gene regulation.

“If you lose this kinase (…) gene expression changes all over the place,” Blind said. “It hasn’t been 100% clear on how all that operates.”

IPMK’s phosphorylated inositol products were known to activate the enzyme histone deacetylase 3, or HDAC3, in laboratory settings. To test this in human cells, Blind’s team deleted IPMK from a brain cancer cell line and saw reduced HDAC3 activity, while other HDACs were unaffected.

Restoring IPMK or adding its inositol products reactivated HDAC3 activity. Blind’s team observed the same phenomenon in noncancerous cells. Since aberrant HDAC3 activity is tied to liver and lung cancers — and drug resistance can reduce HDAC3 therapy effectiveness — targeting IPMK may offer an alternative treatment.

“That's pretty convincing to me that … IPMK inhibitors might in a biomedical sense enhance the selectivity of HDAC3 selective inhibitors in various cancers,” Blind said.

If you missed it, you can watch Blind’s full Breakthroughs webinar here.

Philip Cole

Up next

Chemical approaches to sorting out histone modifications

Aug. 13, 2025, 12:15–1 p.m. Eastern

Philip Cole of Brigham and Women’s Hospital will present his research into the influence of histone modifications on enzyme recognition and processing.

Register for the webinar