# Iron‐Dependent JMJD1A‐Mediated Demethylation of H3K9me2 Regulates Gene Expression During Adipogenesis in a Spatial Genome Organization‐Dependent Manner

## TL;DR

This study shows how the enzyme JMJD1A uses iron to remove a chemical tag from DNA, helping fat cells develop by controlling gene activity in specific regions of the genome.

## Contribution

The study reveals that JMJD1A's iron-dependent demethylation of H3K9me2 regulates adipogenesis in a spatial genome organization-dependent manner.

## Key findings

- JMJD1A knockdown increases H3K9me2 levels, while wild-type JMJD1A reduces them in A compartments.
- JMJD1A targets genes in PPAR signaling and lipid metabolism in an iron-dependent manner.
- Lamin B1 levels decline during differentiation regardless of H3K9me2 status.

## Abstract

Chromatin restructuring across multiple hierarchical scales directs lineage‐specific gene expression during cell differentiation. Here, we investigated the iron‐dependent demethylation of histone H3 lysine 9 dimethylation (H3K9me2) by the demethylase jumonji domain‐containing 1A (JMJD1A) in adipocyte differentiation. Using the 3T3‐L1 adipocyte differentiation model, we show that JMJD1A knockdown increases H3K9me2 levels, whereas forced expression of wild‐type JMJD1A reduces H3K9me2 levels within the A compartment, as defined by megabase scale high‐throughput chromosome conformation capture (Hi‐C) data. In contrast, a JMJD1A mutant defective in iron coordination was unable to demethylate H3K9me2. Genome‐wide analyses of H3K9me2 levels at transcription start sites on a kilobase scale demonstrated that JMJD1A targets genes involved in peroxisome proliferator‐activated receptor signaling and lipid metabolism in an iron‐dependent manner, supporting a model in which H3K9me2 demethylation facilitates adipogenic transcription networks. Furthermore, we examined the relationship between H3K9me2 and lamin B1 levels within lamina‐associated domains (LADs) specifically reorganized during differentiation. Although LADs with higher H3K9me2 exhibited modestly elevated lamin B1 association in preadipocytes, lamin B1 levels declined during differentiation regardless of H3K9me2 status. These findings emphasize the importance of the iron‐dependent enzymatic function in JMJD1A and broaden our understanding of how specific H3K9 demethylases coordinate compartmentalized epigenetic programs during adipogenesis.

JMJD1A‐mediated H3K9me2 demethylation is primarily confined to A compartments on a megabase scale during adipogenesis. Genome‐wide H3K9me2 analysis on a kilobase scale demonstrated that JMJD1A iron‐dependently targets genes involved in PPAR signaling and lipid metabolism.