‘Toxic’ molecules play key role in gene regulation and development – News Center

Molecules once thought to be harmful metabolic byproducts may play important roles in early development and gene regulation, according to a new study published today. nature It challenges decades of biochemical assumptions.

In this study, Northwestern Medicine researchers discovered that L-2-hydroxyglutarate (L-2-HG), a compound previously associated with a rare metabolic disease, functions as a signaling molecule that helps regulate gene expression and supports normal growth in mice.

The findings suggest that some metabolites once thought to be purely toxic may have important physiological functions, said Navdeep Chander, Ph.D., professor of biochemistry and molecular genetics and senior author of the new study.

“This metabolite was previously described as a toxic metabolite and not part of normal physiology,” said Chandel, who is also the David W. Kugel, MD, professor of medicine in the Division of Pulmonary and Critical Care Medicine and Chan Zuckerberg Initiative investigator. “In this case, we found that it is involved in kidney development.”

For many years, L-2-HG was primarily considered a metabolic waste product. In healthy cells, this molecule is kept at very low levels by an enzyme called L-2-HG dehydrogenase (L2HGDH), which converts it to another compound, 2-oxoglutarate. When this process fails in humans, the resulting accumulation of L-2-HG causes neurological disorders in rare cases.

For this reason, scientists have mainly treated L-2-HG as a harmful byproduct. But new research has reconstructed that story.

“We generally think it’s all about our genes, right? Sometimes we turn on genes, and sometimes we turn genes off,” says Chandel. “And then there’s metabolism. It’s just for energy. What we discovered is that mitochondria can also determine these genetic responses. Mitochondria are not just passive players.”

To determine how L‑2‑HG functions, researchers mapped L‑2‑HG interactions with proteins and discovered that L‑2‑HG targets a family of enzymes that modulate gene activity by modifying chromatin.

The researchers, in collaboration with the lab of study co-author Dr. Ali Shilatifard, the Robert Francis Ferchgott Professor of Biochemistry and Molecular Genetics and director of the Simpson Query Epigenetics Laboratory, discovered that L-2‑HG inhibits the KDM4 family of demethylases and increases histone H3K9me3, a repressive histone mark that shuts down gene transcription. At specific sites.

“It blocks transcription by hitting specific H3K9 methylation marks,” said the study’s lead author Ram P. Chakrabarty, Ph.D., a postdoctoral fellow in the Chandel lab.

In mouse embryonic stem cells, increased levels of L‑2‑HG decreased the activity of specific genes, confirming its role as a regulator of gene expression.

“This is an example of a metabolite that we know has nothing to do with ATP production,” says Chandel. “This is a metabolite that exists to transmit information between the mitochondria and the nucleus and determine the fate of the cell.”

Mice engineered to reduce L-2-HG levels during development showed impaired growth, increased mortality, and kidney abnormalities, according to the study.

“This is a metabolite that sends signals and controls physiological functions,” says Chandel. “Because if you just remove that metabolite, you’re going to have obvious kidney pathology.”

Further analysis revealed that low L‑2‑HG disrupts the silencing of retrotransposons, genetic elements that can cause inflammation when activated.

“When you have more of this metabolite, you reduce inflammation. When you have less of this metabolite, it allows these retrotransposons to come in,” he said.

The discovery links metabolism to the control of genomic elements not previously thought to be metabolically regulated, Chandel said. The research also highlights a broader shift in scientific thinking, in which metabolism is not just a support system for cellular function, but the driving force behind it.

“This is probably one of our cleanest examples,” Chandel said. “This molecule is created, does its job, and goes away, and is especially needed for kidney development.”

He added that the discovery opens new directions for research involving retrotransposons in everything from cancer to aging to immune function. It has also been raised that metabolism may play a widespread role in the regulation of retrotransposons, although this concept remains largely unexplored.

Feinberg’s other co-authors include Benjamin Singer (MD 2007, GME 2010, Lawrence Hicks Professor of Pulmonary Medicine); Samuel Weinberg, ’19 MD, ’19 PhD, assistant professor of pathology in the Department of Experimental Pathology. Dr. Aoi Yuki, assistant professor of medicine and biochemistry and molecular genetics. Dr. Fung Yue, Professor of Molecular Medicine Duane Burnham and Professor Susan Burnham. Dr. Yongchao C. Ma, Associate Professor of Pediatrics. Dr. Marta Ivanashko, Research Associate Professor of Biochemistry and Molecular Genetics. Dr. Colleen Reczek, Assistant Professor of Medical Research in the Department of Pulmonary and Critical Care Medicine. Dongmei Wang, PhD, Research Assistant Professor of Pathology. Dr. Peng Gao, Associate Professor of Medicine, Department of Respiratory and Critical Care Medicine. SeungHye Han, MD, MPH, assistant professor of medicine in the Department of Respiratory and Critical Care Medicine. Dr. Sean Davidson, assistant professor of medicine in the Division of Pulmonary and Critical Care Medicine.

This research was supported by National Institutes of Health (NIH) grants: R01CA290678, P01HL071643, P01AG049665, R01HL149883, R01HL153122, P01HL154998, U19AI135964, U19AI181102, R50CA265372, R01AG077451, R01HL172859, P01HL169188, T32HL076139.