Scientists Pinpoint Protein that is Central for Cell Division, Craniofacial Development

May. 2, 2024

A protein originally thought to play a role in tooth structure and development is an essential part of mitosis—the process that allows cells to replicate and the body to grow —according to a new study published in PLOS Biology. Researchers found that if craniofacial development protein 1 (CFDP1) is disrupted, mitosis is disturbed: Only if the protein is intact will mitosis proceed and lead to healthy cell division. The team of scientists from the Eastman Institute for Oral Health at the University of Rochester says the work provides a means to better understand the overall process of development.

Four people standing side-by-side
Study authors (L to R) Gokul Gopinathan, Thomas Diekwisch, Xianghong Luan, and Qian Lu

The research began 25 years ago, when the laboratory of Thomas Diekwisch, D.M.D., Ph.D., Ph.D. discovered and cloned CFDP1, noting its role in survival, differentiation, and proliferation. In 2011, Gokul Gopinathan, a postdoc in Diekwisch’s lab, started searching for the detailed molecular function of CFDP1. Over the course of many years, they discovered that CFDP1 is involved in heterochromatin stability, and that heterochromatin (the mostly untranscribed portion of chromatin), provides anchorage for key mitotic regulators.

“For decades, heterochromatin was not well understood; it was thought to be silent and dubbed the ‘lazy chromatin’ because no one thought it had any function,” noted Diekwisch, senior study author, chair of the Department of Oral and Craniofacial Sciences, and the Margaret and Cy Welcher Professor in Dental Research at the Eastman Institute for Oral Health. “Only recently it has become clear that heterochromatin has many important roles, such as genome organization and duplication. Our work shows how CFDP1 works at the interface between heterochromatin and the mitotic spindle to facilitate cell division.”

In the new study, the team localized CFDP1 as a heterochromatin component essential for structural stability of the centric and pericentric heterochromatin at the centromere region of chromosomes. In the absence of CFDP1, other necessary core heterochromatin components were lost, adversely affecting levels of the gradient protein RanGTP and the essential tubulin spindle nucleator RCC1 at the centromere. The loss of these proteins in turn caused chromosome segregation abnormalities during cell division, resulting in major birth defects in mice lacking CFDP1. 

One of the molecular players involved in mediating the effects of loss of CFDP1 is the variant histone H2A.Z (histones are proteins that DNA wraps around). Fortunately, a unique molecule, the histone chaperon ANP32E allows for the restoration of chromatin H2A.Z levels in cells lacking CFDP1. The authors go on to show that knockdown of both ANP32E and CFDP1 not only alleviated mitosis defects, but also rescued the CFDP1-related birth defects that were found in CFDP1 mutant animals.

“When we began this work, some people thought that CFDP1 was only relevant for the craniofacial region, but it was expressed in many areas of growth throughout the body, which was our first clue that we were up to something,” added Diekwisch.

In addition to Diekwisch, study authors include Gokul Gopinathan and Xianghong Luan; both were members of Diekwisch’s lab when he held positions at Texas A&M University’s College of Dentistry and University of Illinois at Chicago College of Dentistry. Study author Qian Xu recently joined Diekwisch’s lab at the University of Rochester.