Discovering a protein's role in gene expression

November 10, 2017 by Anna Williams, Northwestern University
Credit: CC0 Public Domain

Northwestern Medicine scientists have discovered that a protein called BRWD2/PHIP binds to histone lysine 4 (H3K4) methylation—a key molecular event that influences gene expression—and demonstrated that it does so via a previously uncharacterized protein structural domain.

Beyond providing new insights into the regulation of gene expression, the findings have important implications for several diseases, as BRWD2/PHIP is overexpressed in metastatic melanoma, and mutations in related genes are associated with neuro-developmental syndromes.

The study, published in the journal Genes & Development, was led by Ali Shilatifard, PhD, the Robert Francis Furchgott Professor and chair of Biochemistry and Molecular Genetics. Marc Morgan, PhD, a postdoctoral fellow, was the first author.

Human DNA is wrapped around proteins called histones. When these proteins are modified through a molecular process called histone methylation, they also play a role in determining which genes are turned on or off.

Close to two decades ago, Shilatifard discovered that methylation at a certain histone location called H3K4 is catalyzed by a family of enzymes he named COMPASS. Since then, Shilatifard's laboratory has continued to make extensive discoveries about the process of histone H3K4 methylation, how it controls gene expression, and how its misregulation might give rise to cancer and other disorders.

In the current study, the scientists demonstrated for the first time that the BRWD2/PHIP directly binds to COMPASS-implemented H3K4 methylation in human cancer cells, mouse and Drosophila (fruit flies).

They further discovered that BRWD2/PHIP recognizes the modification through a previously unknown domain of the protein they named the CryptoTudor domain.

"This gives a molecular function to a gene that was on people's radars because of its role in human disease," Morgan said. "We show that it's actually part of a pathway that we know a lot about, and we provide a mechanism for how it binds to a specific substrate."

The scientists demonstrated the findings through a multi-disciplinary approach that took advantage of many state-of-the-art experimental technologies, including CRISPR-Cas9 gene editing, next-generation sequencing, mass spectrometry and biophysical experiments.

The findings are particularly illuminating, Morgan notes, because there is a striking overlap between the conditions affecting individuals who have mutations in the encoding COMPASS and BRWD proteins, such as intellectual disabilities.

"Our thinking is that if COMPASS activity initiates H3K4 methylation, and that's what BRWD2 binds to in the chromatin, then they must be part of the same pathway," Morgan said. "Now, the next big step is to understand precisely what this protein actually does—and that's what we're doing in the lab now."

Future studies, beyond determining the function of BRWD2, will also aim to understand how its binding might help regulate the process of transcriptional control.

"We've found this family of H3K4 binding factors, and we're going to build upon that and determine what they do," said Shilatifard, also a professor of Pediatrics and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. "It's just like a puzzle—before, nothing was fitting in this piece of the puzzle, and now we have a piece that makes sense. Now we have to discover the rest of the puzzle."

Explore further: Unexpected findings uncover new understanding of gene expression

More information: Marc A.J. Morgan et al. A cryptic Tudor domain links BRWD2/PHIP to COMPASS-mediated histone H3K4 methylation, Genes & Development (2017). DOI: 10.1101/gad.305201.117

Related Stories

Unexpected findings uncover new understanding of gene expression

October 2, 2017
Northwestern Medicine scientists have discovered that the catalytic activity of the fly enzyme Trr and mammalian MLL3/MLL4—members of the COMPASS family of proteins central to gene expression—is not required for proper ...

Scientists Discover Mechanism Behind 'Paused' Genes

September 7, 2017
Northwestern Medicine scientists have discovered the mechanism driving a protein that influences transcription, a crucial step in gene expression. The study, recently published in Science, could lead to drugs that control ...

Next-gen reappraisal of interactions within a cancer-associated protein complex

January 15, 2014
At a glance, DNA is a rather simple sequence of A, G, C, T bases, but once it is packaged by histone proteins into an amalgam called chromatin, a more complex picture emerges. Histones, which come in four subtypes—H2A, ...

Recommended for you

Targeting the engine room of the cancer cell

June 18, 2018
Researchers at Columbia University Irving Medical Center (CUIMC) have developed a highly innovative computational framework that can support personalized cancer treatment by matching individual tumors with the drugs or drug ...

Scientists learn more about how gene linked to autism affects brain

June 18, 2018
New preclinical research shows a gene already linked to a subset of people with autism spectrum disorder is critical to healthy neuronal connections in the developing brain, and its loss can harm those connections to help ...

161 genetic factors for myopia identified

June 15, 2018
The international Consortium for Refractive Error and Myopia (CREAM) recently published the largest-ever genetic study of myopia in Nature Genetics. Researchers from the Gutenberg Health Study at the Medical Center of Johannes ...

Genetic disorder identified in children

June 15, 2018
A genetic defect affecting normal development in children has been identified by a study involving University of Queensland researcher and alumnus Professor David Coman.

Scientists discover biomarker for flu susceptibility

June 13, 2018
Researchers at the Stanford University School of Medicine have found a way to predict whether someone exposed to the flu virus is likely to become ill.

Brain secrets that flow in our blood

June 13, 2018
Our blood can be used to uncover genetic secrets inside the brain, according to University of Queensland research.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.