Two Nature Papers Highlight an Understudied Protein

December 15, 2020—(BRONX, NY)—Proteins called histones perform an amazing feat: They so tightly wrap up a cell’s two strands of DNA—each two meters long—that they can fit inside the cell’s tiny nucleus. Chromatin, the name for this complex of DNA and protein, has been likened to “beads on a string.” Each bead, known as a nucleosome, consists of DNA molecules wrapped around histone proteins. Hundreds of thousands of nucleosomes are present in the average human chromosome.

Courtesy: National Human Genome Research Institute
Courtesy: National Human Genome Research Institute
(Click to enlarge)

Over the years, scientists have focused mainly on the four types of histones that intertwine with DNA and form the core of nucleosomes. These “core” histones not only support and package the DNA that constitutes our genes but also are involved in regulating gene expression.

Now, two papers published December 9 in the journal Nature spotlight the importance of a fifth histone protein that binds outside the nucleosome core. Histone H1 is referred to as a “linker” histone because it binds to the nucleosome “beads” and to the DNA “string” linking the nucleosomes. Arthur I. Skoultchi, Ph.D., the Judith and Burton P. Resnick Chair in Cell Biology and chair of the department at Einstein, along with three M.D./Ph.D. students (Michael Willcockson, Sean Healton, and Cary Weiss), and Boris Bartholdy, Ph.D., research assistant professor of cell biology, led one of the studies. A mouse model developed in Dr. Skoultchi’s lab played a key role in the second study.

“We’ve known from previous work in our lab and others that H1 linker histones are required for compacting DNA,” Dr. Skoultchi said, “but we weren’t sure what other functions they might be performing in cells. These two papers show that H1 also contributes to the epigenetic control of gene expression and to cancer prevention.”

Arthur I. Skoultchi, Ph.D.

Arthur I. Skoultchi, Ph.D.

Epigenetic control refers to influences on cells above and beyond those provided by a cell’s DNA genetic code. Research over the past 20 years has shown that histones contain a cell’s so-called epigenetic code. The attachment of certain chemicals (e.g., methyl and acetyl groups) to histones is recognized by a variety of other proteins including so-called “epigenetic readers” and transcription factors, which determine whether or not certain genes will be expressed.

“These histone modifications combine to create an epigenetic code for gene expression,” said Dr. Skoultchi. “Some genes become accessible for transcription, for example, while genes that were accessible may become silenced. We now know that this epigenetic code is important in determining how a human embryo develops, how each cell in the body carries out its specialized function, and how cells age.”

The first Nature paper, on which Dr. Skoultchi was the senior author, described H1’s key role in the epigenetic control of gene expression. He and his co-authors obtained their results after developing a new strain of mice in which they were able to deplete three of the five subtypes of H1 in hematopoietic (blood-forming) cells without killing the mice. Chromatin was found to be especially compacted in areas that were dense with H1; when H1 was depleted, previously silenced T lymphocyte genes present in those chromatin areas became de-repressed (i.e., activated).

This schematic shows the position of a histone H1 'linker' protein in a cell's chromatin. The linker histone is bound to both a nucleosome (composed of 8 “core” histone proteins) and to DNA.
This schematic shows the position of a histone H1 “linker” protein in a cell’s chromatin. The linker histone is bound to both a nucleosome (composed of 8 “core” histone proteins) and to DNA.

“Our results showed that H1 acts as a critical regulator of gene expression through localized control of chromatin compaction, three-dimensional genome organization, and the epigenetic landscape,” said Dr. Skoultchi.

The second study, led by Ari Melnick, M.D., formerly at Einstein and now at Weill Cornell Medical College, addressed H1’s role in human B cell lymphomas, a type of blood cancer. H1 linker histone genes are mutated in about half of those cancers, but it wasn’t clear how the genes contribute to the disease. Using Dr. Skoultchi’s mouse models, Dr. Melnick’s team found that loss of H1 histones can lead to a very similar disease in mice, proving that the presence of H1 histones is important in suppressing cancer.

“These mouse models will help us to better understand how H1 histone mutations contribute to the development of B cell lymphomas,” Dr. Skoultchi said, “and will also be useful for testing specific therapies directed at ‘correcting’ the epigenetic changes that underlie these cancers.”