During embryonic development, cells become increasingly specialized — a process linked to the maturation of the three-dimensional DNA structure and the tightening of chromatin loops. This mechanism, studied in neuronal cells, has been described by the team of Prof. Aleksandra Pękowska, with support from mathematicians.
The team led by Prof. Pękowska, head of the Dioscuri Centre at the Nencki Institute of the Polish Academy of Sciences, examined the maturation of brain cells. “The key to this process lies in changes in the 3D structure of DNA within the cell nucleus,” the researcher explained in an interview with PAP.
A fertilized egg cell is “omnipotent” — it carries the full genetic programs needed to produce any protein encoded in its DNA: rhodopsin for the eye, hemoglobin for the blood, insulin for the pancreas, or oxytocin for the brain. However, during embryogenesis, the cell’s potential narrows. It matures and specializes to perform a specific role in the body. An adult skin cell thus looks and behaves entirely differently from a heart or bone cell — even though they all contain identical DNA. How, then, does a cell “know” its maturity level and identity? And what exactly does maturation mean?
DNA is an extremely long and tangled thread. If the DNA from a single chromosome were straightened, it would measure about 20 centimeters — yet it must fit inside a nucleus only a few micrometers in diameter. It is wound around histones to form chromatin, which is further arranged into loops within the nuclear space. As cells mature, chromatin becomes increasingly organized and consolidated, and the loops tighten.
Researchers have shown for the first time that this consolidation results from the interplay of three elements: the architectural protein CTCF, RNA-binding proteins, and non-coding RNA. The study was published in Nature Cell Biology.
The CTCF protein acts like a zip tie, closing chromatin into precise loops. RNA-binding proteins and non-coding RNA act like glue, stiffening and stabilizing the loops formed by CTCF. As a result, during embryogenesis, the three-dimensional chromatin structure becomes fixed, and the cell’s identity gradually becomes “locked in.”
In the early stages of embryogenesis, loops begin to form but remain loose. As the cell matures — for instance, toward a neuron — these molecular zip ties tighten more and more.
Prof. Pękowska explains that the goal is for key genomic regions — genes and their regulatory elements — to be enclosed within the same loop. This arrangement ensures strict control over gene activity and, consequently, the production of proteins appropriate for each cell type. Genes whose products are unnecessary for a given cell type remain inactive and spatially separated from other genomic regions.
“In the mouse neuronal cells we studied, this consolidation of chromatin structure continues from the first days of embryonic development until birth,” says Prof. Pękowska. “At that point, the cells lose their pluripotency — the ability to become any cell in the organism — and begin to define themselves as more mature forms.”
The team also developed a computational tool capable of estimating cell maturity by measuring how loop-forming proteins are distributed within the nucleus.
“We observed subtle changes in the spatial organization of CTCF within the nucleus as embryogenesis progressed. However, we wanted a rigorous way to describe these differences,” says Prof. Pękowska. She therefore turned to Prof. Paweł Dłotko, a mathematician and computer scientist, head of another Dioscuri Centre at the Institute of Mathematics of the Polish Academy of Sciences.
The mathematicians applied topological data analysis, a branch of mathematics that studies properties of space invariant under stretching or compression. “We developed a tool that allows us to determine a cell’s identity directly from a microscopic image,” explains Prof. Dłotko. “It measures the packing density of DNA material.”
Mathematical analysis (including unsupervised machine learning) clearly demonstrated that, based solely on the distribution of CTCF within the nucleus, one can accurately distinguish between embryonic and more mature cells. This confirmed that changes in CTCF organization are a real, measurable indicator of cellular maturity.
The tool is so universal that it may in the future be used to analyze images of various cell types — not only in basic research but potentially also in diagnostics.
The findings shed new light on diseases linked to abnormal chromatin structure, including CTCF-related syndromes and certain cancers, such as gliomas, which exhibit high activity of one of the non-coding RNAs identified in the study.
This discovery deepens our understanding of how cell identity arises and is maintained — one of the most fundamental processes in biology.
The collaboration was made possible through the Dioscuri Programme, which establishes Centres of Scientific Excellence in Poland in partnership with the Max Planck Society. Prof. Pękowska (a biologist) and Prof. Dłotko (a mathematician) met through this program and realized how their disciplines could complement each other.
They emphasized that such interdisciplinary, high-risk–high-reward projects are crucial for groundbreaking discoveries, though still challenging within the Polish research system. Their success shows the enormous potential of breaking down barriers between disciplines and investing in research at the intersection of diverse scientific fields.
The study also involved Prof. Jeroen Krijgsveld, an expert in proteomic analysis from the German Cancer Research Center in Heidelberg, who helped identify protein partners of CTCF, and Prof. Timo Zimmermann’s team of super-resolution microscopy specialists at the European Molecular Biology Laboratory in Heidelberg, who visualized how CTCF distribution changes during development.
The research was supported by the NCN OPUS grant and the Dioscuri grant.
By Ludwika Tomala (PAP), naukawpolsce.pl
